Gene Summary

Gene:HTRA2; HtrA serine peptidase 2
Aliases: OMI, PARK13, PRSS25
Summary:This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in two transcript variants encoding different isoforms. Additional transcript variants have been described, but their full-length sequences have not been determined. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine protease HTRA2, mitochondrial
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: HTRA2 (cancer-related)

Yang M, Li L, Wang J, et al.
Heterogeneous nuclear ribonucleoproteins (hnRNPs) and human transformer-2-beta1 (hTra2-beta1)-regulated estrogen receptor-alpha improves prognosis of endometrial cancer.
Eur J Gynaecol Oncol. 2014; 35(6):701-7 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: Heterogeneous nuclear ribonucleoprotein (hnRNP) family possesses decreasing effect towards endometrial cancer (EC) and human transformer-2-betal (hTra2-betal) performs an intimate relationship with EC, either. Recent study shows that hnRNPs and hTra2-betal regulate the genetic expression, which is concerned with estrogen receptor (ER).
MATERIALS AND METHODS: The present study was designed to investigate the link between ER and hnRNPs or hTra2-betal in the prognosis of EC patients by Real-time PCR and immunohistochemisty (IHC).
RESULTS: Results showed that ER protein expression presented a significant change in the recurrence and outcome of EC patients, and the nucleus hTra2-betal protein expression was also increased in the recurrent patients, indicating that the three might be important in ER expression in the prognosis therapy of EC patients.
CONCLUSION: The present findings provide an insight of pharmaceutical targeting therapy and prognosis of EC.

Patil KS, Basak I, Lee S, et al.
PARK13 regulates PINK1 and subcellular relocation patterns under oxidative stress in neurons.
J Neurosci Res. 2014; 92(9):1167-77 [PubMed] Related Publications
Parkinson's disease (PD) is a progressive and irreversible neurodegenerative disorder coupled to selective degeneration of dopamine-producing neurons in the substantia nigra. The majority of PD incidents are sporadic, but monogenic cases account for 5-10% of cases. Mutations in PINK1 cause autosomal recessive forms of early-onset PD, and PINK1 stimulates Omi/HtrA2/PARK13 protease activity when both proteins act as neuroprotective components in the same stress pathway. Studies on PINK1 and PARK13 have concentrated on phosphorylation-dependent PINK1-mediated activation of PARK13 and mitochondrial functions, because both proteins are classically viewed as mitochondrial. Although PARK13-mediated protective mechanisms are at least in part regulated by PINK1, little is known concerning how these two proteins are regulated in different subcellular compartments or, indeed, the influence of PARK13 on PINK1 characteristics. We show that PARK13 localizes to a variety of subcellular locations in neuronal cells and that PINK1, although more restrictive, also localizes to locations other than those previously reported. We demonstrate that PARK13 accumulation leads to a concomitant accumulation of PINK1 and that the increase in PINK1 levels is compartmental specific, indicating a correlative relationship between the two proteins. Moreover, we show that PARK13 and PINK1 protein levels accumulate in response to H2 O2 and L-DOPA treatments in a subcellular fashion and that both proteins show relocation to the cytoskeleton in response to H2 O2 . This H2 O2 -mediated relocation is abolished by PARK13 overexpression. This study shows that PARK13 and PINK1 are subcellular-specific, but dynamic, proteins with a reciprocal molecular relationship providing new insight into the complexity of PD.

Zhang F, Yu T, Yi CL, Sun XF
Radiation-inducible HtrA2 gene enhances radiosensitivity of uveal melanoma OCM-1 cells in vitro and in vivo.
Clin Experiment Ophthalmol. 2014; 42(8):761-8 [PubMed] Related Publications
BACKGROUND: To explore an effective approach for the treatment of patients with uveal melanomas, we designed a strategy that combines HtrA2 gene therapy and radiation therapy.
METHODS: pIRES-Egr1-Omi/HtrA2 (pEgr1-HtrA2) recombinant plasmids were constructed and transfected into human uveal melanoma cells (OCM-1) in vitro. The transfected cells were exposed to irradiation. HtrA2 messenger RNA and protein level was detected by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. Combined with radiation, assays that evaluated the apoptotic inducibility caused by HtrA2 gene therapy was performed by flow cytometry. Followingly, the effects of HtrA2 overexpression on the in vitro radiosensitivity of uveal melanoma cells were investigated by clonogenic formation assay. The in vivo effects of HtrA2 gene therapy combined with radiation therapy were evaluated in different groups.
RESULTS: The recombinant plasmids could be successfully transferred into OCM-1 cells, and transfection of pEgr1-HtrA2 plasmids combined with radiotherapy caused dramatically elevation of HtrA2 compared with non-irradiated cells in messenger RNA and protein levels, which was associated with increased apoptosis. Furthermore, we observed that the transfection of pEgr1-HtrA2 could significantly enhance radiosensitivity of OCM-1 cell in vitro. In mice bearing xenograft tumours, pEgr1-HtrA2 combined with radiation therapy significantly inhibited tumour growth compared with the other treatment groups (P < 0.01).
CONCLUSIONS: Our findings indicate that radiation-inducible gene therapy may have potential to be a more effective and specific therapy for uveal melanoma because the therapeutic gene can be spatially or temporally controlled by exogenous radiation.

Krasieva TB, Stringari C, Liu F, et al.
Two-photon excited fluorescence lifetime imaging and spectroscopy of melanins in vitro and in vivo.
J Biomed Opt. 2013; 18(3):31107 [PubMed] Free Access to Full Article Related Publications
Changes in the amounts of cellular eumelanin and pheomelanin have been associated with carcinogenesis. The goal of this work is to develop methods based on two-photon-excited-fluorescence (TPEF) for measuring relative concentrations of these compounds. We acquire TPEF emission spectra (λ(ex)=1000  nm) of melanin in vitro from melanoma cells, hair specimens, and in vivo from healthy volunteers. We find that the pheomelanin emission peaks at approximately 615 to 625 nm and eumelanin exhibits a broad maximum at 640 to 680 nm. Based on these data we define an optical melanin index (OMI) as the ratio of fluorescence intensities at 645 and 615 nm. The measured OMI for the MNT-1 melanoma cell line is 1.6 ± 0.22 while the Mc1R gene knockdown lines MNT-46 and MNT-62 show substantially greater pheomelanin production (OMI=0.5 ± 0.05 and 0.17 ± 0.03, respectively). The measured values are in good agreement with chemistry-based melanin extraction methods. In order to better separate melanin fluorescence from other intrinsic fluorophores, we perform fluorescence lifetime imaging microscopy of in vitro specimens. The relative concentrations of keratin, eumelanin, and pheomelanin components are resolved using a phasor approach for analyzing lifetime data. Our results suggest that a noninvasive TPEF index based on spectra and lifetime could potentially be used for rapid melanin ratio characterization both in vitro and in vivo.

Reiman A, Lu X, Seabra L, et al.
Gene expression and protein array studies of folliculin-regulated pathways.
Anticancer Res. 2012; 32(11):4663-70 [PubMed] Related Publications
The familial cancer syndrome Birt-Hogg-Dube syndrome is characterised by the development of skin (fibrofolliculomas) and renal tumours (and lung cysts) and is caused by mutations in the FLCN tumour suppressor gene. Though the FLCN gene product (folliculin) has been linked to the regulation of a variety of signalling pathways (e.g. the mTOR, AMPK, TGFbeta and hyoxia-responsive genes) the precise function of the folliculin protein is not well-defined. In order to identify potential novel pathways linked to folliculin function we analysed paired isogenic folliculin-deficient and folliculin-expressing cell lines by gene expression and protein (Kinexus) arrays. Gene expression microarray analysis in the folliculin +/- non-renal cancer line (FTC133), revealed 708 differentially expressed targets (fold change >2 and p<0.001) with enrichment of genes in the cadherin and Wnt signalling pathways. Comparison of the differentially expressed genes in the FTC133 datasets and previously reported gene expression data for a folliculin-deficient renal tumour and the UOK257 renal cell carcinoma cell line, revealed that RAB27B was dysregulated in all three datasets (increased expression in folliculin-deficient cells). The Kinexus protein array analysis suggested 73 candidate, differentially expressed, proteins and further investigation by western blot analysis of 5 candidates that were also differentially expressed in the FTC133 gene expression microarray data, revealed that EIF2AK2 (PKR) and CASP1 were reduced and PLCG2 was increased in folliculin-deficient FTC133 cells and in a BHD renal tumour. In view of the role of CASP1 in apoptosis we investigated whether other apoptosis-related proteins might be regulated by folliculin and found increased levels of SMAC/Diablo and HtrA2 in folliculin-expressing FTC133 cells. These findings identify novel pathways and targets linked to folliculin tumour suppressor activity.

Zurawa-Janicka D, Kobiela J, Galczynska N, et al.
Changes in expression of human serine protease HtrA1, HtrA2 and HtrA3 genes in benign and malignant thyroid tumors.
Oncol Rep. 2012; 28(5):1838-44 [PubMed] Related Publications
Human HtrA proteins are serine proteases involved in essential physiological processes. HtrA1 and HtrA3 function as tumor suppressors and inhibitors of the TGF-β signaling pathway. HtrA2 regulates mitochondrial homeostasis and plays a pivotal role in the induction of apoptosis. The aim of the study was to determine whether the HtrA proteins are involved in thyroid carcinogenesis. We used the immunoblotting technique to estimate protein levels of HtrA1, HtrA2, long and short variants of HtrA3 (HtrA3-L and HtrA3-S) and TGF-β1 in tissues of benign and malignant thyroid lesions, and control groups. We found that the levels of HtrA2 and HtrA3-S were higher in thyroid malignant tumors compared to normal tissues and benign tumors. The HtrA3-L level was increased in malignant tumor tissues compared to benign tumor tissues and control tissues from patients with benign lesions, and elevated in normal tissues from patients with thyroid carcinoma compared to normal tissues from patients with benign lesions. We also compared levels of HtrA proteins in follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) and found that these types of carcinoma differed in the expression of HtrA3-S and HtrA1. These results indicate the implication of HtrA proteins in thyroid carcinogenesis suggest that HtrA3 variants may play different roles in cancer development, and that the increased HtrA3-L levels in thyroid tissue could be correlated with the development of malignant lesions. The TGF-β1 levels in tumor tissues were not significantly altered compared to control tissues.

Yoshikawa Y, Morimatsu M, Ochiai K, et al.
Establishment of a PCR analysis method for canine BRCA2.
BMC Res Notes. 2012; 5:173 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mammary tumors are the most common tumor type in both human and canine females. In women, carriers of mutations in BRCA2, a tumor suppressor gene product, have a higher risk of breast cancer. Canine BRCA2 has also been suggested to have a relationship with mammary tumors. However, clearly deleterious BRCA2 mutations have not been identified in any canine mammary tumors, as appropriate methods to detect mutations or a consensus BRCA2 sequence have not been reported.
FINDINGS: For amplification and sequencing of BRCA2, we designed 14 and 20 PCR primer sets corresponding to the BRCA2 open reading frame (ORF) and all 27 exons, respectively, including exon-intron boundaries of the canine BRCA2 regions, respectively. To define the consensus canine BRCA2 ORF sequence, we used established methods to sequence the full-length canine BRCA2 ORF sequence from two ovaries and a testis obtained from individual healthy mongrel dogs and partially sequence BRCA2 genomic sequences in 20-56 tumor-free dogs, each aged over 6 years. Subsequently, we compared these sequences and seven previously reported sequences, and defined the most common base sequences as the consensus canine BRCA2 ORF sequence. Moreover, we established a detection method for identifying splicing variants. Unexpectedly, we also identified novel splicing variants in normal testes during establishment of these methods.
CONCLUSIONS: The present analysis methods for determining the BRCA2 base sequence and for detecting BRCA2 splicing variants and the BRCA2 ORF consensus sequence are useful for better understanding the relationship between canine BRCA2 mutation status and cancer risk.

Omi Y, Shibata N, Okamoto T, et al.
The role of CD147 in the invasiveness of follicular thyroid carcinoma cells.
Thyroid. 2012; 22(4):383-94 [PubMed] Related Publications
BACKGROUND: In patients without metastases, capsular and vascular invasion must be noted to make the diagnosis of follicular thyroid carcinoma (FTC). Some patients are initially diagnosed as follicular adenoma (FA) but develop metastases, indicating the original lesion was FTC. A diagnostic marker for FTCs that appear to be FAs by conventional histopathology is urgently needed. CD147 is a transmembrane glycoprotein that induces matrix metalloproteinases (MMPs) and participates in carcinoma invasion. The objective of this study was to determine whether CD147 is upregulated in FTC and if measures directed against it could reduce the invasive activity of FTC cells.
METHODS: The expression levels of CD147, MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9 in surgical specimens of normal thyroid (n=8), FA (n=20), and FTC (n=9) was determined using immunoblot and immunohistochemical techniques. CD147 protein expression levels of epithelial growth factor stimulated FTC-133 cell lines was measured by immunoblotting with and without cell signaling inhibitors such as wortmannin, PD98059, SP600125, and SB203580. This was also done after exposure to short-hairpin interference RNA directed against CD147.
RESULTS: Immunoblot analysis of thyroid tissues revealed significant increases in signals for CD147, MMP-3, MMP-7, and MMP-9 in FTC compared with FA or normal tissue, or both. Immunohistochemical analysis revealed colocalization of determinants of CD147 with those of all of MMPs studied, mainly in follicular cells in normal and neoplastic cells in FA and FTC; their immunoreactivities were to some extent more intense in the FTC than FA or normals. In FTC-133 cells, immunoreactive signals for CD147 were upregulated by epidermal growth factor (EGF), and the EGF-driven increases in CD147 were prevented by inhibitors against phosphoinositol-3 kinase (PI3K), extracellular signal-regulated protein kinase (ERK), or c-Jun N-terminal kinase (JNK) but not p38. RNA interference targeted against CD147 reduced the invasive activity of FTC-133 cells and was associated with downregulation of MMP-2, MMP-3, MMP-7, and MMP-9.
CONCLUSIONS: These results provide in vivo evidence for CD147 upregulation in FTC and in vitro evidence for EGF-stimulated CD147 induction via the PI3K, ERK, and JNK pathways. They suggest the involvement of CD147 in the invasiveness of FTC cells via regulation of MMPs.

Airiau K, Mahon FX, Josselin M, et al.
ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib.
Exp Hematol. 2012; 40(5):367-78.e2 [PubMed] Related Publications
Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients.

Xu Z, Chen X, Peng C, et al.
Hypoxia-inducible factor-1alpha suppressed hepatocellular carcinoma cell apoptosis through influencing on Omi/HtrA2 expression and its releasing from the mitochondrion.
Oncol Res. 2012; 20(5-6):213-20 [PubMed] Related Publications
Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an important role in regulating hepatoma cell apoptosis. However, conclusions of different studies about the effects of HIF-1alpha expression on hepatoma cell apoptosis remain controversial. Omi/HtrA2 promotes cell apoptosis in some human cancer cells. Our previous experiments have demonstrated that primary hepatocellular carcinoma may need Omi/HtrA2 expression for cell apoptosis. Thus, we investigated the effect of HIF-1alpha on hepatocellular carcinoma cell apoptosis and Omi/ HtrA2 expression. In our study we found that HIF-1alpha gene could suppress hepatoma cell apoptosis, and Omi/HtrA2 mRNA and protein expression decreased with HIF-1alpha expression increase while Bcl-2 mRNA and protein expression increased with HIF-1alpha expression increase in HepG2 cells under normoxia condition. Meanwhile, Omi/HtrA2 protein expression increased with HIF-1alpha expression decrease in HepG2 cells under hypoxia culture. Taken together, these results demonstrated that HIF-1alpha suppressed hepatocellular carcinoma cell apoptosis through inhibiting Omi/HtrA2 expression and upregulating Bcl-2 expression to impede Omi/ HtrA2 releasing from the mitochondrion. The present finding further enriched and supported the role of HIF-1alpha expression on cell apoptosis of hepatoma cells.

Ise N, Omi K, Nambara D, et al.
Overexpressed HER2 in NSCLC is a possible therapeutic target of EGFR inhibitors.
Anticancer Res. 2011; 31(12):4155-61 [PubMed] Related Publications
BACKGROUND: "Oncogene addiction" is a concept in which tumor cells exhibit dependence on certain oncogene(s) for their sustained proliferation and survival, thus providing the rationale for molecular targeted therapies. Cancer cells addicted to epidermal growth factor receptor (EGFR) bear activated mutations in the EGFR gene, and these mutations are used as the markers for predicting carcinomas susceptible to EGFR inhibitors such as gefitinib and erlotinib. However, other unknown mechanisms underlying susceptibility to EGFR inhibitors have also been suggested.
MATERIALS AND METHODS: The susceptibility of non-small-cell lung cancer (NSCLC) cell lines to EGFR inhibitors and the pattern of their oncogene addiction was examined. The effect of EGFR inhibitors on the activation of the oncogene was analyzed. The possible use of the oncogene protein expression as a biomarker was assessed.
RESULTS: HER2 addicted, non-EGFR expressing NSCLC cell line NCI-H2170 was susceptible to EGFR inhibitors. EGFR inhibitor treatment led to markedly decreased phosphorylation levels of activated HER2 and its downstream effector AKT. Furthermore, the soluble form of HER2 was secreted by NCI-H2170 cells and was positively detected in the blood of xenografted mice.
CONCLUSION: HER2 seems to be a valid therapeutic target of EGFR inhibitors in HER2-addicted lung carcinomas, and soluble HER2 may be an effective biomarker to guide the appropriate treatment of such cancer cells.

Yoo BH, Wang Y, Erdogan M, et al.
Oncogenic ras-induced down-regulation of pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells.
J Biol Chem. 2011; 286(45):38894-903 [PubMed] Free Access to Full Article Related Publications
Resistance of carcinoma cells to anoikis, apoptosis that is normally induced by loss of cell-to-extracellular matrix adhesion, is thought to be essential for the ability of these cells to form primary tumors, invade adjacent tissues, and metastasize to distant organs. Current knowledge about the mechanisms by which cancer cells evade anoikis is far from complete. In an effort to understand these mechanisms, we found that ras, a major oncogene, down-regulates protease caspase-2 (which initiates certain steps of the cellular apoptotic program) in malignant human and rat intestinal epithelial cells. This down-regulation could be reversed by inhibition of a protein kinase Mek, a mediator of Ras signaling. We also found that enforced down-regulation of caspase-2 in nonmalignant intestinal epithelial cells by RNA interference protected them from anoikis. Furthermore, the reversal of the effect of Ras on caspase-2 achieved by the expression of exogenous caspase-2 in detached ras-transformed intestinal epithelial cells promoted well established apoptotic events, such as the release of the pro-apoptotic mitochondrial factors cytochrome c and HtrA2/Omi into the cytoplasm of these cells, significantly enhanced their anoikis susceptibility, and blocked their long term growth in the absence of adhesion to the extracellular matrix. Finally, the blockade of the effect of Ras on caspase-2 substantially suppressed growth of tumors formed by the ras-transformed cells in mice. We conclude that ras-induced down-regulation of caspase-2 represents a novel mechanism by which oncogenic Ras protects malignant intestinal epithelial cells from anoikis, promotes their anchorage-independent growth, and allows them to form tumors in vivo.

Matsumoto G, Omi Y, Lee U, et al.
NK4 gene therapy combined with cisplatin inhibits tumour growth and metastasis of squamous cell carcinoma.
Anticancer Res. 2011; 31(1):105-11 [PubMed] Related Publications
BACKGROUND: NK4 inhibits vascularisation in tumour tissues, thereby arresting tumour growth. However, the antitumour efficacy of individual antiangiogenic molecules expressed in vivo is not sufficiently potent to induce regression in animal models. One of the strategies to overcome this disadvantage is to use chemotherapy.
MATERIALS AND METHODS: This study evaluated the efficacy of combining NK4 gene therapy with cisplatin to treat experimental squamous cell carcinomas. For gene therapy, biodegradable cationised gelatin microspheres were used for the controlled release of NK4 plasmid DNA.
RESULTS: A combined regimen of antiangiogenic gene therapy and low-dose cisplatin led to a marked decrease in tumour volume and vascularity, and caused increased apoptosis compared to NK4 gene therapy alone. Moreover, combination treatment of NK4 gene therapy and low-dose cisplatin dramatically inhibited the formation of lung metastases.
CONCLUSION: NK4 gene therapy combined with low-dose cisplatin may be an effective regimen for treating oral squamous cell carcinoma.

Balakrishnan MP, Cilenti L, Ambivero C, et al.
THAP5 is a DNA-binding transcriptional repressor that is regulated in melanoma cells during DNA damage-induced cell death.
Biochem Biophys Res Commun. 2011; 404(1):195-200 [PubMed] Free Access to Full Article Related Publications
THAP5 was originally isolated as a specific interactor and substrate of the mitochondrial pro-apoptotic Omi/HtrA2 protease. It is a human zinc finger protein characterized by a restricted pattern of expression and the lack of orthologs in mouse and rat. The biological function of THAP5 is unknown but our previous studies suggest it could regulate G2/M transition in kidney cells and could be involved in human cardiomyocyte cell death associated with coronary artery disease (CAD). In this report, we expanded our studies on the properties and function of THAP5 in human melanoma cells. THAP5 was expressed in primary human melanocytes as well as in all melanoma cell lines that were tested. THAP5 protein level was significantly induced by UV irradiation or cisplatin treatment, conditions known to cause DNA damage. The induction of THAP5 correlated with a significant increase in apoptotic cell death. In addition, we show that THAP5 is a nuclear protein that could recognize and bind a specific DNA motif. THAP5 could also repress the transcription of a reporter gene in a heterologous system. Our work suggests that THAP5 is a DNA-binding protein and a transcriptional repressor. Furthermore, THAP5 has a pro-apoptotic function and it was induced in melanoma cells under conditions that promoted cell death.

Hartkamp J, Roberts SG
HtrA2, taming the oncogenic activities of WT1.
Cell Cycle. 2010; 9(13):2508-14 [PubMed] Free Access to Full Article Related Publications
Wilms' tumour is a paediatric malignancy of the kidneys and is one of the most common solid childhood cancers. The Wilms' tumour 1 protein (WT1) is a transcription factor that can either activate or repress genes involved in growth, apoptosis and differentiation. It is frequently mutated or aberrantly expressed in Wilms' tumour, where the wild type protein would normally act as a tumour suppressor. Several studies, however, have found that wild type WT1 acts as an oncogene in adult tumours, primarily through the inhibition of apoptosis. The expression of WT1 correlates with the aggressiveness of several adult cancers, and its continued expression following treatment is indicative of a poor outcome.We recently found that the treatment of tumour cell lines with cytotoxic drugs leads to the cleavage of WT1 by the serine protease HtrA2. HtrA2 binds to a specific region of WT1, the suppression domain, and then cleaves WT1 at multiple sites. The HtrA2-mediated proteolysis of WT1 leads to its removal from gene promoter regions and changes in gene expression. Cleavage of WT1 by HtrA2 enhances apoptosis. This event is advantageous to the treatment of adult tumours where WT1 acts as an oncogene. However, when WT1 is acting as a tumour suppressor in paediatric malignancies, proteolysis by HtrA2 would be antagonistic to therapy.

Essafi A, Hastie ND
WT1 the oncogene: a tale of death and HtrA.
Mol Cell. 2010; 37(2):153-5 [PubMed] Related Publications
Here, Hartkamp et al. (2010) identify WT1 as a novel bona fide substrate of the HtrA2/Omi mitochondrial protease and show that this reaction modulates WT1 antiapoptotic activity under cytotoxic stress. This supports an oncogenic function for WT1, with implications for novel chemotherapeutic avenues.

Chien J, Campioni M, Shridhar V, Baldi A
HtrA serine proteases as potential therapeutic targets in cancer.
Curr Cancer Drug Targets. 2009; 9(4):451-68 [PubMed] Free Access to Full Article Related Publications
The human HtrA family of serine proteases consists of four members: HtrA1, HtrA2, HtrA3 and HtrA4. Although prokaryotic HtrA proteins are well characterized in their dual roles as chaperones and proteases that degrade misfolded proteins in the periplasm, some members of mammalian HtrA proteins are described as potential modulators of programmed cell death and chemotherapy-induced cytotoxicity. Goal of this review article is to describe the molecular alterations associated with these HtrA serine proteases and how these alterations may be associated with tumor behavior and response to chemotherapy. We will also discuss evidence that chemotherapeutic drugs regulate the expression and activation of HtrA serine proteases and that these proteases contributes to programmed cell death. Finally, we will discuss the potential role of epigenetic therapy in targeting the expression and activation of HtrA serine proteases and the mechanisms by which these proteases enhance cytotoxic effect of conventional chemotherapy.

Narkiewicz J, Lapinska-Szumczyk S, Zurawa-Janicka D, et al.
Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer.
Oncol Rep. 2009; 21(6):1529-37 [PubMed] Related Publications
The HtrA family of serine proteases takes part in cellular stress response including heat shock, inflammation and cancer. Downregulation of human HtrA1 and HtrA3 genes has been reported in some cancers, including endometrial cancer (EC), suggesting a tumor-suppressor role for both genes. The mechanism of the HtrA function is not known, however, evidence exists showing that both HtrA1 and HtrA3 regulate biological processes by modulating TGF-beta signaling. In the presented study the expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes was examined in 124 endometrial tissue specimens including 88 cancers and 36 normal endometria. The expression of the tested genes was evaluated at mRNA and protein levels by semi-quantitative RT-PCR and western blotting methods, respectively. Our results showed significant decrease of HtrA1 and HtrA3 mRNA and protein levels in EC compared to normal tissues. The most dramatic decrease was found for HtrA3 at both mRNA and protein levels (3.2- and 5.6-fold, respectively). Moreover, the HtrA3 protein (short isoform) was not detected in 19% of the cancers, and its level decreased from the premenopausal to the postmenopausal group. The HtrA2 protein levels were significantly lower in EC tissues compared to normal tissues. We also found a significant increase of the TGF-beta1 protein level in EC as well as a significant negative correlation between HtrA1/2/3 and TGF-beta1 relative protein levels. Our results showing downregulation of HtrA1 and HtrA3 gene expression support previous studies suggesting a tumor suppressor role for these genes. Furthermore, our data suggest that HtrA2 may be involved in EC development as well as suggest the involvement of HtrA1, HtrA2 and HtrA3 in the inhibition of TGF-beta signaling in endometrial tissues.

Su DM, Zhang Q, Wang X, et al.
Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy.
Mol Cancer Ther. 2009; 8(5):1292-304 [PubMed] Free Access to Full Article Related Publications
Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA microarrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A (n = 12) and type B (n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant (P ≤ 0.030; false discovery rate ≤ 3.68%) differences (± ≥ 2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant (P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic (BCL2, BCL2A1, PPARD, and RAF1), antioxidant (MT3, PRDX5, PRDX3, GPX4, GLRX2, and GSR), and proapoptotic (BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1, and VDAC1) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic (PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1), antioxidant (HSPD1, GSS, SOD1, ATOX1, and CAT), and proapoptotic (ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10, and PRODH) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.

Gabriel B, Zur Hausen A, Bouda J, et al.
Significance of nuclear hTra2-beta1 expression in cervical cancer.
Acta Obstet Gynecol Scand. 2009; 88(2):216-21 [PubMed] Related Publications
OBJECTIVE: Human Tra2-beta1, a member of the serine/arginine-rich splicing factors, is involved in C/A-dependent mRNA processing and regulation of gene expression. Since several genes involved in cervical carcinogenesis are alternatively spliced and contain C/A rich elements, we aimed to analyze hTra2-beta1 expression and subcellular localization in tumor tissue of women with cervical cancer and to determine its clinical significance.
DESIGN: Retrospective study.
SETTING: Tertiary-care academic medical center.
SAMPLE: One hundred and five patients with cervical cancer and a mean follow up time of 73.1 months.
METHODS: Immunohistochemistry of paraffin-embedded tissues was performed and hTra2-beta1 expression was correlated with clinico-pathological variables including patient outcome.
RESULTS: Cytoplasmic hTra2-beta1 protein expression was found in 20% of cases, while all tumors revealed nuclear immunoreactivity with strong expression in 54.3% of cases. There was a significant inverse correlation between nuclear and cytoplasmic protein expression, suggesting a potentially relevant shuttle process of hTra2-beta1 between both cellular compartments. Patients with weak expressing hTra2-beta1 tumors showed an improved survival with a tumor-related death rate of 8.3% compared to 23.7% in patients with moderate and high intranuclear hTra2-beta1 expression, respectively.
CONCLUSIONS: Our data support the hypothesis of a biological relevance for hTra2-beta1 expression in cervical cancer. The observed shuttle process of this splicing factor with higher concentrations in the nucleus should have pronounced effects on the cellular function and tumor biology of the affected tumors, leading to the worse patient outcome.

Sánchez Y, Amrán D, Fernández C, et al.
Genistein selectively potentiates arsenic trioxide-induced apoptosis in human leukemia cells via reactive oxygen species generation and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK).
Int J Cancer. 2008; 123(5):1205-14 [PubMed] Related Publications
The observation that genistein may behave as a pro-oxidant agent lead us to examine the capacity of this isoflavone to modulate the toxicity of the oxidation-sensitive anti-leukemic agent arsenic trioxide (ATO), and for comparison other anti-tumor drugs. Co-treatment with genistein increased ATO-provoked apoptosis and activated apoptosis regulatory events (Bcl-X(L) down-regulation, cytochrome c and Omi/HtrA2 release from mitochondria, XIAP decrease and caspase-8/Bid and caspase-3 activation) in U937 promonocytes and other human leukemia cell lines (HL60, THP-1, Jurkat, RPMI-8866), but not in phytohemagglutinin-stimulated non-tumor peripheral blood lymphocytes (PBLs). Genistein, alone and with ATO, stimulated reactive oxygen species generation, and apoptosis was attenuated by N-acetyl-L-cysteine and butylated hydroxyanisole. Addition of low H(2)O(2) concentrations mimicked the capacity of genistein to increase ATO-provoked apoptosis in leukemia cells, but not in PBLs. By contrast, co-treatment with genistein or H(2)O(2) failed to potentiate the toxicity of DNA-targeting agent cisplatin, the proteasome inhibitor MG-132 and the histone deacetylase inhibitor MS-275. Within the here used time-period (14 hr) genistein, alone or with ATO, did not significantly affect Akt phosphorylation and NF-kappaB binding activity, nor decreased intracellular GSH content. However, it elicited N-acetyl-L-cysteine-inhibitable phosphorylation of p38-MAPK and AMPK, and apoptosis was attenuated by pharmacologic inhibitors against these kinases. The pro-oxidant capacity of genistein might be exploited to improve the efficacy of ATO as anti-leukemic agent, and perhaps the efficacy of other oxidation-based therapeutic approaches.

Narkiewicz J, Klasa-Mazurkiewicz D, Zurawa-Janicka D, et al.
Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer.
Clin Biochem. 2008; 41(7-8):561-9 [PubMed] Related Publications
OBJECTIVES: Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes was examined in ovarian tissue specimens including 19 normal ovaries, 20 benign tumors, 7 borderline tumors, 44 cancers and 8 Krukenberg tumors.
DESIGN AND METHODS: mRNA and protein levels were evaluated by semi-quantitative RT-PCR and Western-blotting methods, respectively.
RESULTS: A statistically significant decrease of HtrA1 and HtrA3 expression in ovarian tumors comparing to normal tissues was observed. A dramatic decrease of HtrA3 mRNA and protein levels in all tumor tissue groups, and a loss of HtrA3 protein in 30% malignant tumors were found. A significant decrease of HtrA1 mRNA, and of HtrA3 mRNA and protein in malignant tumors compared to benign tumors was revealed. HtrA2 expression in tumor tissues was slightly decreased. Expression of TGF-beta1 in tumor tissues was not significantly different compared to control tissues.
CONCLUSIONS: Our results show downregulation of HtrA1 and HtrA3 genes' expression in different types of ovarian tumors and give additional evidence that these genes may function as tumor suppressors.

Kempkensteffen C, Hinz S, Christoph F, et al.
Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value.
J Cancer Res Clin Oncol. 2008; 134(5):543-50 [PubMed] Related Publications
PURPOSE: Numerous molecular parameters are thought to be implicated in renal cell carcinoma (RCC) tumor biology and may therefore reflect the malignant potential of individual tumors. Their investigation may thus help to improve the postoperative management of RCC patients. This study characterized the mRNA expression levels and evaluated the prognostic effect of the mitochondrial inhibitor of apoptosis antagonists Smac/DIABLO and Omi/HtrA2 in tumor tissue from clear-cell RCC patients.
METHODS: The relative gene expression (RGE) was analyzed by real-time RT-PCR in tumor tissue obtained from 85 patients (median follow-up: 47 months) following surgical treatment. Expression data was correlated to clinico-pathological variables and outcome.
RESULTS: The RGE of Smac/DIABLO was lowest in patients with primary metastases, intermediate in those who progressed to metastatic disease, and highest in those who did not develop metastases during follow-up (P=0.006). Expression levels of Smac/DIABLO and Omi/HtrA2 were strongly correlated with each other (Pearson coefficient 0.90). Recurrence-free and tumor-specific survival was shorter in patients with low Smac/DIABLO levels (P=0.019 and P=0.001) as well as in those with low Omi/HtrA2 tumor expression (P=0.033 and P=0.032). Contrary to Omi/HtrA2, low Smac/DIABLO levels were still predictive of a reduced time to recurrence (hazard rate 5.31; 95% CI: 1.16-24.21) and tumor-specific survival (hazard rate 4.24; 95% CI: 1.22-14.77) in explorative multivariate analysis.
CONCLUSIONS: The mRNA expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 are strongly inter-correlated, but do not relate to tumor stage or grade of RCC. Our data suggest that expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of RCC patients.

Hunter AM, LaCasse EC, Korneluk RG
The inhibitors of apoptosis (IAPs) as cancer targets.
Apoptosis. 2007; 12(9):1543-68 [PubMed] Related Publications
Apoptosis has been accepted as a fundamental component in the pathogenesis of cancer, in addition to other human diseases including neurodegeneration, coronary disease and diabetes. The origin of cancer involves deregulated cellular proliferation and the suppression of apoptotic processes, ultimately leading to tumor establishment and growth. Several lines of evidence point toward the IAP family of proteins playing a role in oncogenesis, via their effective suppression of apoptosis. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of, and by, the transcription factor NF-kappaB. Thus, when the IAPs are over-expressed or over-active, as is the case in many cancers, cells are no longer able to die in a physiologically programmed fashion and become increasingly resistant to standard chemo- and radiation therapies. To date several approaches have been taken to target and eliminate IAP function in an attempt to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment. In this review, we address IAP proteins as therapeutic targets for the treatment of cancer and emphasize the importance of novel therapeutic approaches for cancer therapy. Novel targets of IAP function are being identified and include gene therapy strategies and small molecule inhibitors that are based on endogenous IAP antagonists. As well, molecular mechanistic approaches, such as RNAi to deplete IAP expression, are in development.

Shankar S, Srivastava RK
Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer.
Int J Oncol. 2007; 30(4):905-18 [PubMed] Related Publications
Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-XL and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidyl-inositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumin-induced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspase-dependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

Kim SJ, Lee SY, Lee C, et al.
Differential expression profiling of genes in a complete hydatidiform mole using cDNA microarray analysis.
Gynecol Oncol. 2006; 103(2):654-60 [PubMed] Related Publications
OBJECTIVES: To gain a better understanding of the genes involved in the pathogenesis of gestational trophoblastic diseases, we evaluated the genome-wide expression levels of genes in complete hydatidiform mole (H-mole) as compared to normal placenta using cDNA microarray technique.
METHODS: The expression profiles of complete H-mole tissues were compared with those of normal placenta using cDNA microarray technique. The data obtained from 10,305 human genes were normalized by the print-tip-based LOWESS method. Significance analysis of microarray (SAM) was used to identify genes with statistically significant changes in expression. The expression levels of genes which showed significant differences between normal early placenta and complete H-mole tissues were further confirmed by RT-PCR.
RESULTS: A cDNA microarray analysis consisting of 10,305 human genes revealed significant changes in the expression of 213 genes, with 91 genes being upregulated and 122 being downregulated. SAM revealed significant changes in gene expression, including those associated with signal transduction, cell structure, transcription, and apoptosis. Further RT-PCR analysis of altered gene expression in mole tissues supported the microarray analysis results. We confirmed the upregulation of TLE4, CAPZA1, PRSS25, RNF130, and USP1 in complete H-mole tissues. Moreover, our study provides the first evidence that ELK3, LAMA3, LNK, STAT2, and TNFRSF25 are downregulated in complete H-mole compared to normal early placenta tissues.
CONCLUSIONS: These findings provide a large body of information regarding gene expression profiles associated with complete H-mole tumorigenesis and allow the identification of potential targets for tumor prevention or therapy.

Watermann DO, Tang Y, Zur Hausen A, et al.
Splicing factor Tra2-beta1 is specifically induced in breast cancer and regulates alternative splicing of the CD44 gene.
Cancer Res. 2006; 66(9):4774-80 [PubMed] Related Publications
The human CD44 gene undergoes extensive alternative splicing of multiple variable exons positioned in a cassette in the middle of the gene. Expression of alternative exons is often restricted to certain tissues and could be associated with tumor progression and metastasis of several human malignancies, including breast cancer. Exon v4 contains multiple copies of a C/A-rich exon enhancer sequence required for optimal inclusion of the exon and binding to the nucleic acid-binding proteins YB-1 and human Tra2-beta1. Here, we show that hTra2-beta1, a member of the extended family of serine/arginine-rich (SR) splicing factors, enhances the in vivo inclusion of CD44 exons v4 and v5. It increased inclusion of exons v4 and v5 and acted synergistically with YB-1. Activation required the C/A-rich enhancer within exon v4. Several other SR proteins had none or only a slight effect on CD44 exon inclusion. In contrast, SC35 inhibited exon usage and antagonized the effects of Tra2 or YB-1. In a matched pair analysis of human breast cancers and their corresponding nonpathologic tissue controls, we found a significant induction of Tra2-beta1 in invasive breast cancer, both on the RNA and protein levels. Together with our functional data, these results suggest an important role for Tra2-beta1 in breast cancer. Induction of this splicing factor might be responsible for splicing of CD44 isoforms associated with tumor progression and metastasis.

Fandy TE, Shankar S, Ross DD, et al.
Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma.
Neoplasia. 2005; 7(7):646-57 [PubMed] Free Access to Full Article Related Publications
In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21(WAF1) and p27(Kip1) expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, and PUMA), the downregulation of the anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-X(L)), and IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NF(kappa)B activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.

Suganuma H, Kumada M, Omi T, et al.
Aly/ REF, a factor for mRNA transport, activates RH gene promoter function.
FEBS J. 2005; 272(11):2696-704 [PubMed] Related Publications
The rhesus (Rh) blood group antigens are of considerable importance in transfusion medicine as well as in newborn or autoimmune hemolytic diseases due to their high antigenicity. We identified a major DNaseI hypersensitive site at the 5' flanking regions of both RHD and RHCE exon 1. A 34 bp fragment located at -191 to -158 from a translation start position, and containing the TCCCCTCCC sequence, was involved in enhancing promoter activity, which was assessed by luciferase reporter gene assay. A biotin-labelled 34 bp probe isolated an mRNA transporter protein, Aly/REF. The specific binding of Aly/REF to RH promoter in erythroid was confirmed by chromatin immunoprecipitation assay. The silencing of Aly/REF by siRNA reduced not only the RH promoter activity of the reporter gene but also transcription from the native genome. These facts provide second proof of Aly/REF as a transcription coactivator, initially identified as a coactivator for the TCRalpha enhancer function. Aly/REF might be a novel transcription cofactor for erythroid-specific genes.

Philchenkov A, Zavelevich M, Kroczak TJ, Los M
Caspases and cancer: mechanisms of inactivation and new treatment modalities.
Exp Oncol. 2004; 26(2):82-97 [PubMed] Related Publications
Elimination of superfluous or mutated somatic cells is provided by various mechanisms including apoptosis. Deregulation of apoptotic signaling pathways may contribute to oncogenesis. Aspartate specific cysteine proteases, termed caspases are the key effector molecules in apoptosis. The aim of this review is to summarize the various defects in caspase-dependent cell death machinery identified in the neoplastic cells. These include not only mutations, but also alterations of gene methylation, and altered mRNA stability. Among the molecules that we discuss are elements of the extrinsic death pathway like CD95 (APO-1/Fas), FADD, FLIPs, FLICE, other apical caspases, components of the intrinsic apoptotic pathway like Apaf-1, caspase-9, and modulators of apoptotic pathways like IAPs, Smac/DIABLO, OMI/HtrA2, and other apoptosis regulating proteins. We also discuss recent data on cancer-specific agents that target effector mechanisms of apoptosis. Particular emphasis is given to the prospects for combining cell suicide-activating approaches with classical cancer therapies.

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