ALDH3A1

Gene Summary

Gene:ALDH3A1; aldehyde dehydrogenase 3 family member A1
Aliases: ALDH3, ALDHIII
Location:17p11.2
Summary:Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-derived acetaldehyde and in the metabolism of corticosteroids, biogenic amines, neurotransmitters, and lipid peroxidation. The enzyme encoded by this gene forms a cytoplasmic homodimer that preferentially oxidizes aromatic and medium-chain (6 carbons or more) saturated and unsaturated aldehyde substrates. It is thought to promote resistance to UV and 4-hydroxy-2-nonenal-induced oxidative damage in the cornea. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:aldehyde dehydrogenase, dimeric NADP-preferring
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ALDH3A1 (cancer-related)

Leung AW, Hung SS, Backstrom I, et al.
Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro.
PLoS One. 2016; 11(3):e0150675 [PubMed] Free Access to Full Article Related Publications
Platinum-based combination chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). While cisplatin is effective, its use is not curative and resistance often emerges. As a consequence of microenvironmental heterogeneity, many tumour cells are exposed to sub-lethal doses of cisplatin. Further, genomic heterogeneity and unique tumor cell sub-populations with reduced sensitivities to cisplatin play a role in its effectiveness within a site of tumor growth. Being exposed to sub-lethal doses will induce changes in gene expression that contribute to the tumour cell's ability to survive and eventually contribute to the selective pressures leading to cisplatin resistance. Such changes in gene expression, therefore, may contribute to cytoprotective mechanisms. Here, we report on studies designed to uncover how tumour cells respond to sub-lethal doses of cisplatin. A microarray study revealed changes in gene expressions that occurred when A549 cells were exposed to a no-observed-effect level (NOEL) of cisplatin (e.g. the IC10). These data were integrated with results from a genome-wide siRNA screen looking for novel therapeutic targets that when inhibited transformed a NOEL of cisplatin into one that induced significant increases in lethality. Pathway analyses were performed to identify pathways that could be targeted to enhance cisplatin activity. We found that over 100 genes were differentially expressed when A549 cells were exposed to a NOEL of cisplatin. Pathways associated with apoptosis and DNA repair were activated. The siRNA screen revealed the importance of the hedgehog, cell cycle regulation, and insulin action pathways in A549 cell survival and response to cisplatin treatment. Results from both datasets suggest that RRM2B, CABYR, ALDH3A1, and FHL2 could be further explored as cisplatin-enhancing gene targets. Finally, pathways involved in repairing double-strand DNA breaks and INO80 chromatin remodeling were enriched in both datasets, warranting further research into combinations of cisplatin and therapeutics targeting these pathways.

Stavrinou P, Mavrogiorgou MC, Polyzoidis K, et al.
Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors.
PLoS One. 2015; 10(11):e0143285 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3) and some of their proteins.
METHODS: Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary.
RESULTS: Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas.
CONCLUSIONS: The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.

Zhang X, Yang XR, Sun C, et al.
Promyelocytic leukemia protein induces arsenic trioxide resistance through regulation of aldehyde dehydrogenase 3 family member A1 in hepatocellular carcinoma.
Cancer Lett. 2015; 366(1):112-22 [PubMed] Related Publications
Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down-regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combined with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression.

Chakrabarti S, Multani S, Dabholkar J, Saranath D
Whole genome expression profiling in chewing-tobacco-associated oral cancers: a pilot study.
Med Oncol. 2015; 32(3):60 [PubMed] Related Publications
The current study was undertaken with a view to identify differential biomarkers in chewing-tobacco-associated oral cancer tissues in patients of Indian ethnicity. The gene expression profile was analyzed in oral cancer tissues as compared to clinically normal oral buccal mucosa. We examined 30 oral cancer tissues and 27 normal oral tissues with 16 paired samples from contralateral site of the patient and 14 unpaired samples from different oral cancer patients, for whole genome expression using high-throughput IlluminaSentrix Human Ref-8 v2 Expression BeadChip array. The cDNA microarray analysis identified 425 differentially expressed genes with >1.5-fold expression in the oral cancer tissues as compared to normal tissues in the oral cancer patients. Overexpression of 255 genes and downregulation of 170 genes (p < 0.01) were observed. Further, a minimum twofold overexpression was observed in 32 genes and downregulation in 12 genes, in 30-83% of oral cancer patients. Biological pathway analysis using Kyoto Encyclopedia of Genes and Genome Pathway database revealed that the differentially regulated genes were associated with critical biological functions. The biological functions and representative deregulated genes include cell proliferation (AIM2, FAP, TNFSF13B, TMPRSS11A); signal transduction (FOLR2, MME, HTR3B); invasion and metastasis (SPP1, TNFAIP6, EPHB6); differentiation (CLEC4A, ELF5); angiogenesis (CXCL1); apoptosis (GLIPR1, WISP1, DAPL1); and immune responses (CD300A, IFIT2, TREM2); and metabolism (NNMT; ALDH3A1). Besides, several of the genes have been differentially expressed in human cancers including oral cancer. Our data indicated differentially expressed genes in oral cancer tissues and may identify prognostic and therapeutic biomarkers in oral cancers, postvalidation in larger numbers and varied population samples.

Ding Y, Yang M, She S, et al.
iTRAQ-based quantitative proteomic analysis of cervical cancer.
Int J Oncol. 2015; 46(4):1748-58 [PubMed] Related Publications
Cervical cancer is the seventh most common cancer overall and the third among females. To obtain systematic insight into the protein profile that participates in cervical tumor oncogenesis and improve the current target therapies, iTRAQ labeling and NanoLC-MS/MS analysis were utilized to detect differentially expressed proteins in cervical cancer. As a result, 3,647 proteins were identified, among which the expression levels of 294 proteins in cervical cancer samples were distinct from the paired non-tumor samples. Further validation of the differentially expressed proteins, including G6PD, ALDH3A1, STAT1 and HSPB1, was carried out via qRT-PCR, western blot analysis and tissue microarray. Functional analysis of one of the highly expressed proteins, G6PD, was performed using RNA interference. Attenuated G6PD expression reduced the capacity of HeLa cells to migrate and invade in vitro. Our investigation complemented the understanding of cervical cancer progression. Furthermore, the present study supports the notion that suppressing the expression of G6PD may be a promising strategy in developing novel cancer therapeutic drugs.

Brauze D, Fijalkiewicz K, Szaumkessel M, et al.
Diversified expression of aryl hydrocarbon receptor dependent genes in human laryngeal squamous cell carcinoma cell lines treated with β-naphthoflavone.
Toxicol Lett. 2014; 231(1):99-107 [PubMed] Related Publications
The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. In this study the effect of administration of β-naphthoflavone (BNF), potent AhR ligand, on the expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1, NQO1, GSTA1, ALDH3A1 and UGT1A genes encoding the enzymes controlled by AhR were examined in thirteen laryngeal tumor cell lines and in HepaRG cell line. The analyzed cell lines were derived from patients with squamous laryngeal cancer, with history of cigarette smoking and without signs of human papillomavirus types 16 and 18 infection in investigated cells. Quantitative real-time RT-PCR analysis revealed huge interindividual differences in expression of genes from AhR regulatory network. Our results strongly suggest predominant effect of DNA methylation on induction of CYP1A1 expression by AhR ligands as well. Our results indicate that differentiated HepaRG cell line appeared to be very good substitute for human liver in studies on xenobiotic metabolism by AhR regulated enzymes.

Tang X, Kuhlenschmidt TB, Li Q, et al.
A mechanically-induced colon cancer cell population shows increased metastatic potential.
Mol Cancer. 2014; 13:131 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis accounts for the majority of deaths from cancer. Although tumor microenvironment has been shown to have a significant impact on the initiation and/or promotion of metastasis, the mechanism remains elusive. We previously reported that HCT-8 colon cancer cells underwent a phenotypic transition from an adhesive epithelial type (E-cell) to a rounded dissociated type (R-cell) via soft substrate culture, which resembled the initiation of metastasis. The objective of current study was to investigate the molecular and metabolic mechanisms of the E-R transition.
METHODS: Global gene expressions of HCT-8 E and R cells were measured by RNA Sequencing (RNA-seq); and the results were further confirmed by real-time PCR. Reactive oxygen species (ROS), anoikis resistance, enzyme activity of aldehyde dehydrogenase 3 family, member A1 (ALDH3A1), and in vitro invasion assay were tested on both E and R cells. The deformability of HCT-8 E and R cells was measured by atomic force microscopy (AFM). To study the in vivo invasiveness of two cell types, athymic nude mice were intra-splenically injected with HCT-8 E or R cells and sacrificed after 9 weeks. Incidences of tumor development and metastasis were histologically evaluated and analyzed with Fisher's exact test.
RESULTS: Besides HCT-8, E-R transition on soft substrates was also seen in three other cancer cell lines (HCT116, SW480 colon and DU145 prostate cancer). The expression of some genes, such as ALDH3A1, TNS4, CLDN2, and AKR1B10, which are known to play important roles in cancer cell migration, invasion, proliferation and apoptosis, were increased in HCT-8 R cells. R cells also showed higher ALDH3A1 enzyme activity, higher ROS, higher anoikis resistance, and higher softness than E cells. More importantly, in vitro assay and in vivo animal models revealed that HCT-8 R cells were more invasive than E cells.
CONCLUSIONS: Our comprehensive comparison of HCT-8 E and R cells revealed differences of molecular, phenotypical, and mechanical signatures between the two cell types. To our knowledge, this is the first study that explores the molecular mechanism of E-R transition, which may greatly increase our understanding of the mechanisms of cancer mechanical microenvironment and initiation of cancer metastasis.

Yan J, De Melo J, Cutz JC, et al.
Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis.
Br J Cancer. 2014; 110(10):2593-603 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear.
METHODS: ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression.
RESULTS: In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated.
CONCLUSIONS: We report here the association of ALDH3A1 with PC progression.

Parajuli B, Georgiadis TM, Fishel ML, Hurley TD
Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity.
Chembiochem. 2014; 15(5):701-12 [PubMed] Free Access to Full Article Related Publications
Aldehyde dehydrogenase 3A1 (ALDH3A1) plays an important role in many cellular oxidative processes, including cancer chemoresistance, by metabolizing activated forms of oxazaphosphorine drugs such as cyclophosphamide (CP) and its analogues, such as mafosfamide (MF), ifosfamide (IFM), and 4-hydroperoxycyclophosphamide (4-HPCP). Compounds that can selectively target ALDH3A1 could permit delineation of its roles in these processes and could restore chemosensitivity in cancer cells that express this isoenzyme. Here we report the detailed kinetic and structural characterization of an ALDH3A1-selective inhibitor, CB29, previously identified in a high-throughput screen. Kinetic and crystallographic studies demonstrate that CB29 binds within the aldehyde substrate-binding site of ALDH3A1. Cellular proliferation of ALDH3A1-expressing lung adenocarcinoma (A549) and glioblastoma (SF767) cell lines, as well as ALDH3A1 non-expressing lung fibroblast (CCD-13Lu) cells, is unaffected by treatment with CB29 and its analogues alone. However, sensitivity toward the anti-proliferative effects of mafosfamide is enhanced by treatment with CB29 and its analogue in the tumor cells. In contrast, the sensitivity of CCD-13Lu cells toward mafosfamide was unaffected by the addition of these same compounds. CB29 is chemically distinct from the previously reported small-molecule inhibitors of ALDH isoenzymes and does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 isoenzymes at concentrations up to 250 μM. Thus, CB29 is a novel small molecule inhibitor of ALDH3A1, which might be useful as a chemical tool to delineate the role of ALDH3A1 in numerous metabolic pathways, including sensitizing ALDH3A1-positive cancer cells to oxazaphosphorines.

Shahdoust M, Hajizadeh E, Mozdarani H, Chehrei A
Finding genes discriminating smokers from non-smokers by applying a growing self-organizing clustering method to large airway epithelium cell microarray data.
Asian Pac J Cancer Prev. 2013; 14(1):111-6 [PubMed] Related Publications
BACKGROUND: Cigarette smoking is the major risk factor for development of lung cancer. Identification of effects of tobacco on airway gene expression may provide insight into the causes. This research aimed to compare gene expression of large airway epithelium cells in normal smokers (n=13) and non-smokers (n=9) in order to find genes which discriminate the two groups and assess cigarette smoking effects on large airway epithelium cells.
MATERIALS AND METHODS: Genes discriminating smokers from non-smokers were identified by applying a neural network clustering method, growing self-organizing maps (GSOM), to microarray data according to class discrimination scores. An index was computed based on differentiation between each mean of gene expression in the two groups. This clustering approach provided the possibility of comparing thousands of genes simultaneously.
RESULTS: The applied approach compared the mean of 7,129 genes in smokers and non-smokers simultaneously and classified the genes of large airway epithelium cells which had differently expressed in smokers comparing with non-smokers. Seven genes were identified which had the highest different expression in smokers compared with the non-smokers group: NQO1, H19, ALDH3A1, AKR1C1, ABHD2, GPX2 and ADH7. Most (NQO1, ALDH3A1, AKR1C1, H19 and GPX2) are known to be clinically notable in lung cancer studies. Furthermore, statistical discriminate analysis showed that these genes could classify samples in smokers and non-smokers correctly with 100% accuracy. With the performed GSOM map, other nodes with high average discriminate scores included genes with alterations strongly related to the lung cancer such as AKR1C3, CYP1B1, UCHL1 and AKR1B10.
CONCLUSIONS: This clustering by comparing expression of thousands of genes at the same time revealed alteration in normal smokers. Most of the identified genes were strongly relevant to lung cancer in the existing literature. The genes may be utilized to identify smokers with increased risk for lung cancer. A large sample study is now recommended to determine relations between the genes ABHD2 and ADH7 and smoking.

Smith PJ, Wiltshire M, Chappell SC, et al.
Kinetic analysis of intracellular Hoechst 33342--DNA interactions by flow cytometry: misinterpretation of side population status?
Cytometry A. 2013; 83(1):161-9 [PubMed] Related Publications
We outline a simple approach involving instrument setup and calibration for the analysis of Hoechst dye 33342-loading in human cell lines for exploring heterogeneity in dye efflux efficiency and the status of side population (SP) A549 lung cancer cells. Dual excitation 488 nm/multiline UV (351-364 nm) flow cytometry was used to confirm ABCG2-specific inhibition of dye efflux using Fumitremorgin C. Transporter gene expression, assayed by qRT-PCR, confirmed higher expression of ABCG2 versus ABCB1, reiterated in a cloned subline. Coexpression of aldehyde dehydrogenase genes ranked as aldehyde dehydrogenase class 1A1 (ALDH1A1) > ALDH3A1 > ALDH3, relative expression of all genes was again reiterated in a cloned subline. Permeabilized cells were used to create red:violet (660:405 nm Em wavelengths) ratiometric references for mapping temporal changes in Hoechst 33342-DNA fluorescence in live cells. A live cell "kinetic SP gate" tracked progressive dye loading of the whole population and coapplication of the far red (>695 nm wavelength) fluorescing dye DRAQ7 enabled viable cell gating. Kinetic gating revealed a continuum for dye accumulation suggesting that SP enumeration is critically dependent upon the nonlinear relationship of the spectral shift with progressive dye-DNA binding and thus requires accurate definition. To this end, permeabilized cell reference samples permit reproducible instrument setup, guide gate boundaries for SP and compromised cells, and offer a simple means of comparing SP enumeration across laboratory sites/platforms. Our approach reports the dynamic range for the spectral shift, revealing noninformative staining conditions and explaining a source of variability for SP enumeration. We suggest that live cell kinetic sorting of all cells with the same dye:DNA load but with differences in efflux capacity can be used to explore drug resistance capability without prejudice. The SP phenotype should be regarded as a kinetic parameter and not a fixed characteristic--critical for functional assay design and the interpretation of heterogeneity.

Susaki Y, Inoue M, Minami M, et al.
Inhibitory effect of PPARγ on NR0B1 in tumorigenesis of lung adenocarcinoma.
Int J Oncol. 2012; 41(4):1278-84 [PubMed] Related Publications
NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor γ (PPARγ) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARγ was examined. The transactivation ability of PPARγ was inhibited by NR0B1 in lung adenocarcinoma, and the N-terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co-immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARγ. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARγ overexpression. ALDH activity increased by treatment with PPARγ inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARγ expression was a negative prognostic factor in Pathological-Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARγ on the malignant grade of lung adenocarcinoma.

Sudhir PR, Chen CH, Pavana Kumari M, et al.
Label-free quantitative proteomics and N-glycoproteomics analysis of KRAS-activated human bronchial epithelial cells.
Mol Cell Proteomics. 2012; 11(10):901-15 [PubMed] Free Access to Full Article Related Publications
Mutational activation of KRAS promotes various malignancies, including lung adenocarcinoma. Knowledge of the molecular targets mediating the downstream effects of activated KRAS is limited. Here, we provide the KRAS target proteins and N-glycoproteins using human bronchial epithelial cells with and without the expression of activated KRAS (KRAS(V12)). Using an OFFGEL peptide fractionation and hydrazide method combined with subsequent LTQ-Orbitrap analysis, we identified 5713 proteins and 608 N-glycosites on 317 proteins in human bronchial epithelial cells. Label-free quantitation of 3058 proteins (≥2 peptides; coefficient of variation (CV) ≤ 20%) and 297 N-glycoproteins (CV ≤ 20%) revealed the differential regulation of 23 proteins and 14 N-glycoproteins caused by activated KRAS, including 84% novel ones. An informatics-assisted IPA-Biomarker® filter analysis prioritized some of the differentially regulated proteins (ALDH3A1, CA2, CTSD, DST, EPHA2, and VIM) and N-glycoproteins (ALCAM, ITGA3, and TIMP-1) as cancer biomarkers. Further, integrated in silico analysis of microarray repository data of lung adenocarcinoma clinical samples and cell lines containing KRAS mutations showed positive mRNA fold changes (p < 0.05) for 61% of the KRAS-regulated proteins, including biomarker proteins, CA2 and CTSD. The most significant discovery of the integrated validation is the down-regulation of FABP5 and PDCD4. A few validated proteins, including tumor suppressor PDCD4, were further confirmed as KRAS targets by shRNA-based knockdown experiments. Finally, the studies on KRAS-regulated N-glycoproteins revealed structural alterations in the core N-glycans of SEMA4B in KRAS-activated human bronchial epithelial cells and functional role of N-glycosylation of TIMP-1 in the regulation of lung adenocarcinoma A549 cell invasion. Together, our study represents the largest proteome and N-glycoproteome data sets for HBECs, which we used to identify several novel potential targets of activated KRAS that may provide insights into KRAS-induced adenocarcinoma and have implications for both lung cancer therapy and diagnosis.

Poage GM, Butler RA, Houseman EA, et al.
Identification of an epigenetic profile classifier that is associated with survival in head and neck cancer.
Cancer Res. 2012; 72(11):2728-37 [PubMed] Free Access to Full Article Related Publications
Panels of prognostic biomarkers selected using candidate approaches often do not validate in independent populations, so additional strategies are needed to identify reliable classifiers. In this study, we used an array-based approach to measure DNA methylation and applied a novel method for grouping CpG dinucleotides according to well-characterized genomic sequence features. A hypermethylation profile among 13 CpG loci, characterized by polycomb group target genes, mammalian interspersed repeats, and transcription factor-binding sites (PcG/MIR/TFBS), was associated with reduced survival (HR, 3.98; P = 0.001) in patients with head and neck squamous cell carcinoma. This association was driven by CpGs associated with the TAP1 and ALDH3A1 genes, findings that were validated in an independent patient group (HR, 2.86; P = 0.04). Together, the data not only elucidate new potential targets for therapeutic intervention in head and neck cancer but also may aid in the identification of poor prognosis patients who may require more aggressive treatment regimens.

Muzio G, Maggiora M, Paiuzzi E, et al.
Aldehyde dehydrogenases and cell proliferation.
Free Radic Biol Med. 2012; 52(4):735-46 [PubMed] Related Publications
Aldehyde dehydrogenases (ALDHs) oxidize aldehydes to the corresponding carboxylic acids using either NAD or NADP as a coenzyme. Aldehydes are highly reactive aliphatic or aromatic molecules that play an important role in numerous physiological, pathological, and pharmacological processes. ALDHs have been discovered in practically all organisms and there are multiple isoforms, with multiple subcellular localizations. More than 160 ALDH cDNAs or genes have been isolated and sequenced to date from various sources, including bacteria, yeast, fungi, plants, and animals. The eukaryote ALDH genes can be subdivided into several families; the human genome contains 19 known ALDH genes, as well as many pseudogenes. Noteworthy is the fact that elevated activity of various ALDHs, namely ALDH1A2, ALDH1A3, ALDH1A7, ALDH2*2, ALDH3A1, ALDH4A1, ALDH5A1, ALDH6, and ALDH9A1, has been observed in normal and cancer stem cells. Consequently, ALDHs not only may be considered markers of these cells, but also may well play a functional role in terms of self-protection, differentiation, and/or expansion of stem cell populations. The ALDH3 family includes enzymes able to oxidize medium-chain aliphatic and aromatic aldehydes, such as peroxidic and fatty aldehydes. Moreover, these enzymes also have noncatalytic functions, including antioxidant functions and some structural roles. The gene of the cytosolic form, ALDH3A1, is localized on chromosome 17 in human beings and on the 11th and 10th chromosome in the mouse and rat, respectively. ALDH3A1 belongs to the phase II group of drug-metabolizing enzymes and is highly expressed in the stomach, lung, keratinocytes, and cornea, but poorly, if at all, in normal liver. Cytosolic ALDH3 is induced by polycyclic aromatic hydrocarbons or chlorinated compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, in rat liver cells and increases during carcinogenesis. It has been observed that this increased activity is directly correlated with the degree of deviation in hepatoma and lung cancer cell lines, as is the case in chemically induced hepatoma in rats. High ALDH3A1 expression and activity have been correlated with cell proliferation, resistance against aldehydes derived from lipid peroxidation, and resistance against drug toxicity, such as oxazaphosphorines. Indeed, cells with a high ALDH3A1 content are more resistant to the cytostatic and cytotoxic effects of lipidic aldehydes than are those with a low content. A reduction in cell proliferation can be observed when the enzyme is directly inhibited by the administration of synthetic specific inhibitors, antisense oligonucleotides, or siRNA or indirectly inhibited by the induction of peroxisome proliferator-activated receptor γ (PPARγ) with polyunsaturated fatty acids or PPARγ transfection. Conversely, cell proliferation is stimulated by the activation of ALDH3A1, whether by inhibiting PPARγ with a specific antagonist, antisense oligonucleotides, siRNA, or a medical device (i.e., composite polypropylene prosthesis for hernia repair) used to induce cell proliferation. To date, the mechanisms underlying the effects of ALDHs on cell proliferation are not yet fully clear. A likely hypothesis is that the regulatory effect is mediated by the catabolism of some endogenous substrates deriving from normal cell metabolism, such as 4-hydroxynonenal, which have the capacity to either stimulate or inhibit the expression of genes involved in regulating proliferation.

Afsar NA, Ufer M, Haenisch S, et al.
Relationship of drug metabolizing enzyme genotype to plasma levels as well as myelotoxicity of cyclophosphamide in breast cancer patients.
Eur J Clin Pharmacol. 2012; 68(4):389-95 [PubMed] Related Publications
PURPOSE: The cytotoxic drug cyclophosphamide (CP) is bioactivated into 4-hydroxy-cyclophosphamide (4-OH-CP) through cytochrome P450 enzymes and cleared through aldehyde dehydrogenase and glutathione S-transferase. This prospective study analyzes the influence of drug metabolizing enzyme genotype on (1) plasma 4-OH-CP:CP ratio and (2) myelotoxicity in breast cancer patients on 500 mg/m(2) cyclophosphamide.
METHODS: Sixty-eight female breast cancer patients on FAC (fluorouracil, adriamycin, cyclophosphamide) were included. Genotyping of cytochrome P450 enzymes CYP2B6, CYP2C9, CYP2C19, CYP3A5, aldehyde dehydrogenase (ALDH3A1), and glutathione S-transferase (GSTA1) was done either through RFLP or pyrosequencing. Plasma CP and 4-OH-CP were measured immediately and 1 and 2 h after the end of infusion through LC-MS. The leukocyte count was determined on day 10 and 20 after chemotherapy.
RESULTS: At CP dose of 500 mg/m(2), the 4-OH-CP:CP ratio was negatively affected by CYP2C19*2 genotype (p = 0.039) showing a gene-dose effect. Moreover ALDH3A1*2 genotype increased 4-OH-CP:CP ratio (p = 0.037). These effects did not remain significant in a univariate analysis of variance including all genotypes. GSTA1*B carriers were at increased risk of severe leucopenia (OR 6.94; 95% CI 1.75-27.6, p = 0.006).
CONCLUSION: The myelotoxicity in patients receiving FAC is related to the activity of the phase-II enzyme GSTA1 but is independent of the formation of 4-OH-CP.

Chiang CP, Jao SW, Lee SP, et al.
Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer.
Alcohol. 2012; 46(1):37-49 [PubMed] Related Publications
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1>ALDH2>ADH3≈ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.

Zhang F, Song C, Ma Y, et al.
Effect of fibroblasts on breast cancer cell mammosphere formation and regulation of stem cell-related gene expression.
Int J Mol Med. 2011; 28(3):365-71 [PubMed] Related Publications
The purpose of this study was to investigate the regulatory effects of breast cancer fibroblasts (BCFs) vs. normal mammary fibroblasts (NMFs) on mammosphere formation and stem cell-related gene expression in breast cancer cells. Breast cancer cells (MCF-7) were cultured in suspension to generate primary and secondary mammospheres. The proportion of CD44+/CD24low/- cells was assessed by flow cytometry (FCM), and Wnt1, Notch1, β-catenin, CXCR4, SOX2 and ALDH3A1 gene expression was detected by quantitative real-time PCR. The fibroblasts from either breast cancer tissue or normal mammary tissue were purified from tissue specimens and co-cultured with breast cancer cells. The mammosphere formation efficacy was approximately 180/10,000 MCF-7 cells. FCM analysis showed that, compared to the 2.1% positive expression in the MCF-7 monolayer culture cells, the expression of CD44+/CD24low/- in MCF-7 mammosphere cells was significantly elevated to 10.4% (P<0.01). The proportion of the CD44+/CD24low/- subpopulation of the cells in mammospheres was nearly 5-fold higher than that of general MCF-7 cells. Compared with MCF-7 monolayer culture cells, mammosphere cells showed significantly (P<0.01) enhanced expression of Wnt1 [fold-change (FC), 2.25], Notch1 (FC, 2.45), β-catenin (FC, 1.72), CXCR4 (FC, 4.68), SOX2 (FC, 4.25) and ALDH3A1 (FC, 5.38). When BCFs were co-cultured with MCF-7 cells under mammosphere culture conditions, the length of time of mammosphere formation decreased, the volume of the mammo-spheres increased and the mammosphere-forming efficiency (MFE) was higher than that of NMFs and the control group. Both the BCF and NMF groups showed enhanced gene expression for the following genes: Wnt1 (FC, 3.18 and 1.27, respectively), β-catenin (FC, 1.75 and 1.22, respectively), Notch1 (FC, 2.09 and 1.31, respectively), CXCR4 (FC, 2.77 and 1.33, respectively), SOX2 (FC, 2.77 and 1.80, respectively) and ALDH3A1 (FC, 5.23 and 1.85, respectively). Cancer fibroblast cells can promote the MFE and up-regulate stem cell-related gene expression in breast cancer cells.

Berger MJ, Minnerath SR, Adams SD, et al.
Gene expression changes with differentiation of cord blood stem cells to respiratory epithelial cells: a preliminary observation.
Stem Cell Res Ther. 2011; 2(2):19 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Owing to wide availability, low cost and avoidance of ethical concerns, umbilical cord blood (UCB) provides an attractive source of stem cells for investigational and therapeutic uses. In this study, we sought to characterize the gene expression changes as stem cells from UCB differentiate toward alveolar type II pneumocytes (ATII).
METHODS: Control and experimental cells were cultured in maintenance medium (mesenchymal stem cell growth medium) or differentiation medium (small airway growth medium (SAGM)), respectively, for 8 days. Total RNA was isolated from control and experimental groups for gene expression profiling and real-time polymerase chain reaction assay.
RESULTS: Analysis of only mixed cell lines (n = 2) with parameters including a P value of 0.01 and an intergroup gap of 2.0 yielded a set of 373 differentially expressed genes. Prominently upregulated genes included several genes associated with ATII cells and also lung cancers: ALDH3A1, VDR and CHKA. Several upregulated genes have been shown to be integral or related to ATII functioning: SGK1, HSD17B11 and LEPR. Finally, several upregulated genes appear to play a role in lung cancers, including FDXR and GP96. Downregulated genes appear to be associated with bone, muscle and central nervous system tissues as well as other widespread tissues.
CONCLUSIONS: To the best of our knowledge, this accounting of the gene expression changes associated with the differentiation of a human UCB-derived stem cell toward an ATII cell represents the first such effort. Dissecting which components of SAGM affect specific gene regulation events is warranted.

Sullivan JP, Spinola M, Dodge M, et al.
Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.
Cancer Res. 2010; 70(23):9937-48 [PubMed] Free Access to Full Article Related Publications
Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH(+) lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH(-) counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH(+) cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH(+) lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH(+) component, implicating Notch signaling in lung cancer stem cell maintenance.

Afsar NA, Haenisch S, Mateen A, et al.
Genotype frequencies of selected drug metabolizing enzymes and ABC drug transporters among breast cancer patients on FAC chemotherapy.
Basic Clin Pharmacol Toxicol. 2010; 107(1):570-6 [PubMed] Related Publications
Polymorphic genes of drug metabolizing enzymes and transporters may influence drug response. With some exemptions, single nucleotide polymorphisms in such genes, however, are not known to be susceptibility factors for breast cancer. This study explored genotype profiles for the breast cancer patients on fluorouracil, doxorubicin and cyclophosphamide (FAC) in a Pakistani set of population and their comparison with HapMap data. Sixty-eight female breast cancer patients were included. All received FAC chemotherapy. Relevant genotyping was done either through restriction fragment length polymorphism or pyrosequencing. The variant allele frequencies were: 5.1% for CYP2C9*2 (430C>T), 15.4% for CYP2C9*3 (1075A>C), 27.2% for CYP2C19*2 (681G>A), 33.1% for GSTA1*B (-69C>T, -52G>A), 62.5% for ALDH3A1*2 (985C>G), 58.8% and 4.4% for ABCB1 (2677 G>T/A), 64.7% for ABCB1 3435 C>T, and 15.4%, 33.1% and 39.7% for ABCC2 (-24 C>T, 1249 G>A and 3972 C>T). In comparison with HapMap, this first exploration in Pakistani samples shows higher frequency of (i) CYP2C9*3 carriers (p < 0.05) than in Hispanic, Chinese, Japanese and African samples, (ii) ALDH3A1*2 carriers (p < 0.01) than Caucasian, Hispanic, Chinese, Japanese and African samples. For ABC transporters, a higher frequency of variant allele was observed in (iii) ABCB1 2677 G>T/A (p < 0.01) than Caucasian, Hispanic and African, (iv) ABCB1 3435 C>T (p < 0.05) than Chinese, Japanese and African, (v) ABCC2 1249 G>A (p < 0.01) than Hispanic, Chinese and Japanese samples. In conclusion, cyclophosphamide activation and detoxification of reactive intermediates may be altered in the Pakistani. Though carriers of CYP2C19*2 were higher than in Caucasian and Hispanics, they did not reach statistical significance (p = 0.05).

Searles Nielsen S, McKean-Cowdin R, Farin FM, et al.
Childhood brain tumors, residential insecticide exposure, and pesticide metabolism genes.
Environ Health Perspect. 2010; 118(1):144-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Insecticides that target the nervous system may play a role in the development of childhood brain tumors (CBTs). Constitutive genetic variation affects metabolism of these chemicals.
METHODS: We analyzed population-based case-control data to examine whether CBT is associated with the functional genetic polymorphisms PON1C-108T, PON1Q192R, PON1L55M, BCHEA539T, FMO1C-9536A, FMO3E158K, ALDH3A1S134A, and GSTT1 (null). DNA was obtained from newborn screening archives for 201 cases and 285 controls, RESULTS: We observed no biologically plausible main effects for any of the metabolic polymorphisms with CBT risk. However, we observed strong interactions between genotype and insecticide exposure during childhood. Among exposed children, CBT risk increased per PON1-108T allele [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.1-3.0] and FMO1-9536A (*6) allele (OR = 2.7; 95% CI, 1.2-5.9), whereas among children never exposed, CBT risk was not increased (PON1: OR = 0.7; 95% CI, 0.5-1.0, interaction p = 0.005; FMO1: OR = 1.0; 95% CI, 0.6-1.6, interaction p = 0.009). We observed a similar but statistically nonsignificant interaction between childhood exposure and BCHEA539T (interaction p = 0.08). These interactions were present among both Hispanic and non-Hispanic white children.
CONCLUSION: Based on known effects of these variants, these results suggest that exposure in childhood to organophosphorus and perhaps to carbamate insecticides in combination with a reduced ability to detoxify them may be associated with CBT. Confirmation in other studies is required.

Stagos D, Chen Y, Cantore M, et al.
Corneal aldehyde dehydrogenases: multiple functions and novel nuclear localization.
Brain Res Bull. 2010; 81(2-3):211-8 [PubMed] Free Access to Full Article Related Publications
Aldehyde dehydrogenases (ALDHs) represent a superfamily of NAD(P)(+)-dependent enzymes which catalyze the oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding acids. Some ALDHs have been identified as corneal crystallins and thereby contribute to the protective and refractive properties of the cornea. ALDH3A1 is highly expressed in the cornea of most mammals with the exception of rabbit that abundantly expresses ALDH1A1 in the cornea instead of ALDH3A1. In this study, we examined the gene expression of other ALDHs and found high messenger levels of ALDH1B1, ALDH2 and ALDH7A1 in mouse cornea and lens. Substantial evidence supports a protective role for ALDH3A1 and ALDH1A1 against ultraviolet radiation (UVR)-induced oxidative damage to ocular tissues. The mechanism by which this protection occurs includes UVR filtering, detoxification of reactive aldehydes generated by UVR exposure and antioxidant activity. We recently have identified ALDH3A1 as a nuclear protein in corneal epithelium. Herein, we show that ALDH3A1 is also found in the nucleus of rabbit keratocytes. The nuclear presence of ALDH3A1 may be involved in cell cycle regulation.

Low SK, Kiyotani K, Mushiroda T, et al.
Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients.
J Hum Genet. 2009; 54(10):564-71 [PubMed] Related Publications
Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.

Chiang CP, Wu CW, Lee SP, et al.
Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human pancreas: implications for pathogenesis of alcohol-induced pancreatic injury.
Alcohol Clin Exp Res. 2009; 33(6):1059-68 [PubMed] Related Publications
BACKGROUND: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are major enzymes responsible for metabolism of ethanol. Genetic polymorphisms of ADH1B, ADH1C, and ALDH2 occur among racial populations. The metabolic effect and metabolites contribute to pathogenesis of pancreatic injury. The goal of this study was to determine the functional expressions and cellular localization of ADH and ALDH families in human pancreas.
METHODS: Fifty five surgical specimens of normal pancreas as well as 15 samples each for chronic pancreatitis and pancreatic cancer from archival formalin-fixed paraffin-embedded tissue specimens were investigated. Class-specific antibodies were prepared by affinity chromatographies from rabbit antisera raised against recombinant human ADH1C1, ADH4, ADH5, ADH7, ALDH1A1, ALDH2, and ALDH3A1. The isozyme expression patterns of ADH/ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting, and the cellular localizations were detected by immunohistochemistry and histochemistry.
RESULTS: At 33 mM ethanol, pH 7.5, the activities were significantly different between allelic phenotypes of ADH1B. The activity of ALDH2-inactive phenotypes was slightly lower than ALDH2-active phenotypes at 200 microM acetaldehyde. The protein contents were in the following decreasing order: ALDH1A1, ALDH2, ADH1, and ADH5. ADH1B was detected in the acinar cells and ADH1C in the ductular, islet, and stellate cells. The expression of ADH1C appeared to be increased in the activated pancreatic stellate cells in chronic pancreatitis and pancreatic cancer.
CONCLUSIONS: Alcohol dehydrogenase and ALDH family members are differentially expressed in the various cell types of pancreas. ADH1C may play an important role in modulation of activation of pancreatic stellate cells.

Hingorani P, Zhang W, Piperdi S, et al.
Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma.
Cancer Chemother Pharmacol. 2009; 64(4):733-40 [PubMed] Related Publications
PURPOSE: Oxazaphosphorines, such as ifosfamide (IFA), are frequently used in the treatment of pediatric sarcomas. They are pro-drugs and undergo hepatic metabolism into the active moiety and potentially toxic by-products such as acrolein and chloracetaldehyde, which may cause hemorrhagic cystitis and encephalopathy, respectively. In addition, resistance to oxazaphosphorines can be mediated by overexpression of enzymes involved in their catabolism. Isophosphoramide mustard (IPM, palifosfamide) is the active moiety of IFA. In the current study, the activity of palifosfamide lysine (ZIO-201), a stable form of palifosfamide, was evaluated in a panel of sarcoma cell lines and tumor xenografts including oxazaphosphorine-resistant xenografts.
METHODS: The cytotoxic effect of palifosfamide lysine was studied in osteosarcoma (OS), Ewing's sarcoma (ES) and rhabdomyosarcoma (RMS) cell lines using the MTT assay. In vivo, the maximum tolerated dose (MTD) of palifosfamide lysine was determined in SCID mice based on a 3-day intravenous (IV) administration schedule. The effect on tumor growth and event-free survival was assessed at the MTD in all three sarcoma xenografts. In OS, cyclophosphamide (CPA)-resistant and -sensitive xenografts (OS31 and OS33, respectively) were evaluated for palifosfamide lysine activity. ALDH1A1 and ALDH3A1 gene expression data for the OS xenografts were mined from the Pediatric Preclinical Testing Program gene expression data. ALDH3A1 enzyme levels were compared between the CPA-resistant and -sensitive xenografts.
RESULTS: Palifosfamide lysine was cytotoxic against all the cell lines tested with the IC(50) ranging from 0.5 to 1.5 microg/ml except for OS222, which had an IC(50) of 7 microg/ml. The IV MTD of palifosfamide lysine in mice was 100 mg/kg per day for three consecutive days. Tumor growth inhibition was seen in both OS31 and OS33 xenografts and the RMS xenograft resulting in a significant difference in event-free survival between the control and the treated groups. Differential gene expression of ALDH3A1 but not ALDH1A1 was noted in the OS31 xenograft. This was confirmed by RT-PCR and the ALDH3A1 enzyme assay. ALDH3A1 enzyme activity was measured at 100 mIU/mg of protein in OS31 xenograft but no significant activity was seen in the OS33 xenograft.
CONCLUSIONS: We conclude that palifosfamide lysine has broad activity in a panel of sarcoma cell lines. It inhibits tumor growth in OS and RMS xenografts. Furthermore, it is active against the CPA-resistant, ALDH3A1 overexpressing, OS xenograft suggesting that it might have the potential of overcoming this resistance mechanism against oxazaphosphorines and may be an active agent in resistant/relapsed sarcomas in patients.

Hu G, Chong RA, Yang Q, et al.
MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.
Cancer Cell. 2009; 15(1):9-20 [PubMed] Free Access to Full Article Related Publications
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.

Moreb JS, Baker HV, Chang LJ, et al.
ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells.
Mol Cancer. 2008; 7:87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aldehyde dehydrogenase isozymes ALDH1A1 and ALDH3A1 are highly expressed in non small cell lung cancer. Neither the mechanisms nor the biologic significance for such over expression have been studied.
METHODS: We have employed oligonucleotide microarrays to analyze changes in gene profiles in A549 lung cancer cell line in which ALDH activity was reduced by up to 95% using lentiviral mediated expression of siRNA against both isozymes (Lenti 1+3). Stringent analysis methods were used to identify gene expression patterns that are specific to the knock down of ALDH activity and significantly different in comparison to wild type A549 cells (WT) or cells similarly transduced with green fluorescent protein (GFP) siRNA.
RESULTS: We confirmed significant and specific down regulation of ALDH1A1 and ALDH3A1 in Lenti 1+3 cells and in comparison to 12 other ALDH genes detected. The results of the microarray analysis were validated by real time RT-PCR on RNA obtained from Lenti 1+3 or WT cells treated with ALDH activity inhibitors. Detailed functional analysis was performed on 101 genes that were significantly different (P < 0.001) and their expression changed by > or = 2 folds in the Lenti 1+3 group versus the control groups. There were 75 down regulated and 26 up regulated genes. Protein binding, organ development, signal transduction, transcription, lipid metabolism, and cell migration and adhesion were among the most affected pathways.
CONCLUSION: These molecular effects of the ALDH knock-down are associated with in vitro functional changes in the proliferation and motility of these cells and demonstrate the significance of ALDH enzymes in cell homeostasis with a potentially significant impact on the treatment of lung cancer.

Ekhart C, Rodenhuis S, Smits PH, et al.
Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.
Pharmacogenet Genomics. 2008; 18(11):1009-15 [PubMed] Related Publications
PURPOSE: High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool.
EXPERIMENTAL DESIGN: We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC.
RESULTS: Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1A1*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13, 95% CI: 1.30-20.30; P=0.02). No other relations reached significance.
CONCLUSION: Patients heterozygous for the ALDH3A1*2 and ALDH1A1*2 allele have an increased risk of haemorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy.

Ekhart C, Doodeman VD, Rodenhuis S, et al.
Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide.
Pharmacogenet Genomics. 2008; 18(6):515-23 [PubMed] Related Publications
PURPOSE: The anticancer agent, cyclophosphamide, is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. Polymorphisms of these enzymes may affect the pharmacokinetics of cyclophosphamide and thereby its toxicity and efficacy. The purpose of this study was to evaluate the effects of known allelic variants in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes on the pharmacokinetics of the anticancer agent, cyclophosphamide, and its active metabolite 4-hydroxycyclophosphamide.
EXPERIMENTAL DESIGN: A cohort of 124 Caucasian patients received a high-dose chemotherapy combination consisting of cyclophosphamide (4-6 g/m2), thiotepa (320-480 mg/m2) and carboplatin (area under the curve 13-20 mg x min/ml) as intravenous infusions over 4 consecutive days. Genomic DNA was analysed using PCR and sequencing. Liquid chromatography-tandem mass spectrometry was used to measure plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide. The relationship between allelic variants and the elimination pharmacokinetic parameters noninducible cyclophosphamide clearance (CL(nonind)), inducible cyclophosphamide clearance (CL(ind)) and elimination rate constant of 4-hydroxycyclophosphamide (k(4OHCP)) were evaluated using nonlinear mixed effects modelling.
RESULTS: The interindividual variability in the noninducible cyclophosphamide clearance, inducible cyclophosphamide clearance and 4-hydroxycyclophosphamide clearance was 23, 27 and 31%, respectively. No effect of the allelic variants investigated on the clearance of cyclophosphamide or 4-hydroxycyclophosphamide could be demonstrated.
CONCLUSION: This study indicates that the presently evaluated variant alleles in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes do not explain the interindividual variability in cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics and are, probably, not the cause of the observed variability in toxicity.

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