Gene Summary

Gene:AIFM1; apoptosis inducing factor mitochondria associated 1
Summary:This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells, and it is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the translocation of this protein to the nucleus where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Mutations in this gene cause combined oxidative phosphorylation deficiency 6 (COXPD6), a severe mitochondrial encephalomyopathy, as well as Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4), a disorder resulting in neuropathy, and axonal and motor-sensory defects with deafness and cognitive disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 10. [provided by RefSeq, Aug 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:apoptosis-inducing factor 1, mitochondrial
Source:NCBIAccessed: 29 August, 2019


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 (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 29 August, 2019 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: AIFM1 (cancer-related)

Saeinasab M, Bahrami AR, González J, et al.
SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF.
J Exp Clin Cancer Res. 2019; 38(1):172 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Thousands of long noncoding RNAs (lncRNAs) are aberrantly expressed in various types of cancers, however our understanding of their role in the disease is still very limited.
METHODS: We applied RNAseq analysis from patient-derived data with validation in independent cohort of patients. We followed these studies with gene regulation analysis as well as experimental dissection of the role of the identified lncRNA by multiple in vitro and in vivo methods.
RESULTS: We analyzed RNA-seq data from tumors of 456 CRC patients compared to normal samples, and identified SNHG15 as a potentially oncogenic lncRNA that encodes a snoRNA in one of its introns. The processed SNHG15 is overexpressed in CRC tumors and its expression is highly correlated with poor survival of patients. Interestingly, SNHG15 is more highly expressed in tumors with high levels of MYC expression, while MYC protein binds to two E-box motifs on SNHG15 sequence, indicating that SNHG15 transcription is directly regulated by the oncogene MYC. The depletion of SNHG15 by siRNA or CRISPR-Cas9 inhibits cell proliferation and invasion, decreases colony formation as well as the tumorigenic capacity of CRC cells, whereas its overexpression leads to opposite effects. Gene expression analysis performed upon SNHG15 inhibition showed changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3 or ERBB3. Several of these genes are functionally related to AIF, a protein that we found to specifically interact with SNHG15, suggesting that the SNHG15 acts, at least in part, by regulating the activity of AIF. Interestingly, ROS levels, which are directly regulated by AIF, show a significant reduction in SNHG15-depleted cells. Moreover, knockdown of SNHG15 increases the sensitiveness of the cells to 5-FU, while its overexpression renders them more resistant to the chemotherapeutic drug.
CONCLUSION: Altogether, these results describe an important role of SNHG15 in promoting colon cancer and mediating drug resistance, suggesting its potential as prognostic marker and target for RNA-based therapies.

Chen W, Liu H, Wang T, et al.
Downregulation of AIF-2 Inhibits Proliferation, Migration, and Invasion of Human Glioma Cells via Mitochondrial Dysfunction.
J Mol Neurosci. 2019; 68(2):304-310 [PubMed] Related Publications
Glioma remains the leading cause of brain tumor-related death worldwide. Apoptosis inducing factor (AIF) is a family of mitochondrial oxidoreductases that play important roles in mitochondrial metabolism and redox control. AIF-1 has been demonstrated to exert cell-killing effect via apoptosis in cancer cells, whereas the role of AIF-2 in cancer cells has not been determined. This study aimed to investigate the role of AIF-2 in human glioma cells. We found that AIF-2 was upregulated in human glioma tissues and cell lines, especially in U251 cells. Downregulation of AIF-2 using specific siRNA (Si-AIF-2) significantly reduced cell proliferation, induced G1 cell cycle arrest and differently regulated the expression of cell cycle regulator proteins in U251 cells. In addition, the results of Matrigel invasion assay and live-cell tracking assay showed that knockdown of AIF-2 inhibited cell invasion and migration. The results of immunocytochemistry indicated that knockdown of AIF-2 significantly attenuated the nuclear translocation of AIF-1, which was confirmed by western blot analysis. Furthermore, downregulation of AIF-2 resulted in mitochondrial dysfunction in U251 cells, as evidenced by reduced mitochondrial membrane potential (MMP), mitochondrial complex I activity, and mitochondrial Ca

Li D, Li X, Li G, et al.
Alpinumisoflavone causes DNA damage in Colorectal Cancer Cells via blocking DNA repair mediated by RAD51.
Life Sci. 2019; 216:259-270 [PubMed] Related Publications
AIMS: Colorectal Cancer (CRC) accounts for 6.1% incidence and 9.2% mortality worldwide. The current study aimed to investigate the effect of alpinumisoflavone (AIF) on CRC and its possible molecular mechanism.
METHODS: HCT-116 and SW480 cells were chosen as cell model to study the anti-cancer activity of AIF in vitro experiments. Cells proliferative capacity and clonogenicity were examined by CCK-8 assay and colony formation assay, while cell apoptosis was detected by Hoechst 33258 staining and Flow cytometer. The protein expression levels of related gene were examined by western blotting. Transcriptome analyses were conducted to identify the differentially expressed genes in CRC cells, following AIF treatment. DNA damage was examined by γH2AX foci assay. The anti-cancer effect of AIF in vivo was validated in CRC xenograft model.
KEY FINDINGS: We found that AIF inhibited CRC cell proliferation and promoted apoptosis in a dose-dependent manner, as well as increased the number of γ-H2AX foci. In addition, microarray analysis showed that the DNA-double strand break (DSB) repair gene RAD51 was aberrantly overexpressed in CRC tissues, and was positively correlated with lymph node metastasis, TNM stage and poor outcomes. Both in vitro and in vivo experiments confirm that AIF treatment significantly decreased RAD51 levels. Knockdown RAD51 could enhance the anti-cancer activity of AIF against CRC, while abrogated by RAD51 overexpression.
SIGNIFICANCE: These findings suggest that AIF can be regarded as a potential anti-cancer drug and provide new insights into CRC treatment.

Zhang C, Hao Y, Wu L, et al.
Curcumin induces apoptosis and inhibits angiogenesis in murine malignant mesothelioma.
Int J Oncol. 2018; 53(6):2531-2541 [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin‑induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase‑independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

Jang B, Kim LH, Lee SY, et al.
Trichostatin A induces apoptosis in oral squamous cell carcinoma cell lines independent of hyperacetylation of histones.
J Cancer Res Ther. 2018; 14(Supplement):S576-S582 [PubMed] Related Publications
Aim of Study: To investigate the apoptotic event of trichostatin A (TSA) and its associated mechanism in oral squamous cell carcinoma (OSCC) lines.
Materials and Methods: HSC-3 and Ca9.22 cell lines were evaluated using a trypan blue exclusion assay, histone isolation, soft agar assay, live/dead assay, 4%,6-diamidino-2-phenylindole staining, JC-1 mitochondrial membrane potential (MMP) assay, and Western blot analysis to demonstrate the anticancer activity of TSA.
Results: TSA decreased OSCC cell viability and proliferation without affecting the histone acetylation. TSA-induced caspase-dependent or -independent apoptosis according to cell types, TSA enhanced the expression levels of Bim protein by dephosphorylating ERK1/2 pathway in HSC-3 cells. TSA also damaged MMP and increased cytosolic apoptosis-inducing factor (AIF) in Ca9.22 cells.
Conclusion: The present study suggests that TSA may be a potential anticancer drug candidate for the treatment of OSCC through the induction of apoptosis.

Ernst EH, Lykke-Hartmann K
Transcripts encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles.
J Assist Reprod Genet. 2018; 35(10):1787-1798 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: To study the presence and distribution of genes encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles.
METHODS: A class comparison study on existing granulosa cell transcriptome from primordial (n = 539 follicles) and primary (n = 261) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy was performed and interrogated.
RESULTS: In granulosa cells from primordial follicles, 30 genes were annotated 'mitochondrial dysfunction' including transcripts (PRDX5, TXN2) encoding enzymatic free radical scavengers peroxiredoxin 5 and thioredoxin 2. Several apoptosis regulation genes were noted (BCL2, CAS8, CAS9, AIFM1). In granulosa cells from primary follicles, mitochondrial dysfunction signalling pathway was annotated. High expression of transcripts encoding the free radical scavenger peroxiredoxin 3, as well as anti-apoptotic enzyme BCL2, was found. Interestingly, PARK7 encoding the deglycase (DJ-1) protein was expressed in granulosa cells from primary follicles. DJ-1 is implicated in oxidative defence and functions as a positive regulator of the androgen receptor and as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/serine-threonine protein kinase (AKT) signalling pathway suppressor PTEN.
CONCLUSIONS: The results indicate extensive energy production and free radical scavenging in the granulosa cells of primordial follicles with potential implications for ovarian ageing, cigarette smoking, premature ovarian failure and polycystic ovarian syndrome. Furthermore, DJ-1 may be involved in androgen responsiveness and the regulation of follicle growth via PI3K/PTEN/AKT signalling pathway regulation in the granulosa cells of primary follicles. The involvement of mitochondrial free radical production in the age-related decline of competent oocytes is becoming apparent.

Wang M, Liu Y, Qian X, et al.
Downregulation of occludin affects the proliferation, apoptosis and metastatic properties of human lung carcinoma.
Oncol Rep. 2018; 40(1):454-462 [PubMed] Related Publications
Lung cancer is the most frequent and deadliest cancer in the world, especially in China. However, the molecular mechanisms involved in lung cancer remain unclear. Occludin (OCLN), one of the first identified tight junction proteins, has been revealed to be a necessary integral protein for tight junction structure and function. In the present study, we investigated the role of occludin in lung tumorigenesis. We found that occludin protein expression was highly increased in human lung cancer patient samples. Western blotting results also revealed that occludin expression was different in several lung cancer cell lines, with the highest level in SPC‑A1 cells. Moreover, occludin knockdown inhibited lung cancer cell proliferation in vitro and in vivo. In addition, occludin knockdown promoted the apoptosis of lung cancer cell lines and reduced the invasion ability. Mechanistically, the activity of key growth pathway AKT/PI3K was compromised after occludin knockdown. Expression of apoptosis‑related proteins, BAX, caspase‑3, caspase‑9 and AIF, but not Bcl‑2, were upregulated after silencing of occludin. Collectively, our findings for the first time identify the role of occludin as a tumor promoter and a pro‑metastatic factor in lung cancer, demonstrating that occludin is a potential prognostic biomarker and therapeutic target in lung cancer.

Liu D, Liu M, Wang W, et al.
Overexpression of apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) induces apoptosis by promoting the transcription of caspase3 and DRAM in hepatoma cells.
Biochem Biophys Res Commun. 2018; 498(3):453-457 [PubMed] Related Publications
Full-length apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) (∼67 kDa) induces apoptosis in a caspase-independent manner when it is cleaved at its N-terminus to produce truncated AIFM1 (∼57 kDa). Here, we produced recombinant adenovirus AIFM1 (rAd-AIFM1) encoding full-length AIFM1 to detect whether full-length AIFM1 suppresses cell growth and induces apoptosis of hepatoma cell lines (HepG2 and Hep3B). Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat worldwide. The MTT assay demonstrated that full-length AIFM1 inhibited the growth of hepatoma cells because rAd-AIFM1 infection suppressed the proliferation of HepG2 and Hep3B cells. TUNEL assay demonstrated that full-length AIFM1 overexpression induced apoptosis in HepG2 and Hep3B cells infected with rAd-AIFM1, suggesting an apoptosis-inducing ability of full-length AIFM1. Our data further showed that the expression of two pro-apoptotic genes, caspase3 and DRAM, were involved in full-length AIFM1 infection-induced apoptosis, and full-length AIFM1 could also positively regulate the transcription of caspase3 and DRAM. Thus, overexpression of full-length AIFM1 can induce caspase-dependent apoptosis and suppresses cell growth of hepatoma cells. Our data uncover a potential role of rAd-AIFM1 in HCC gene therapy.

Ferrero H, Díaz-Gimeno P, Sebastián-León P, et al.
Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment.
Reproduction. 2018; 155(4):373-381 [PubMed] Related Publications
Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 (

Li F, Zhao D, Yang S, et al.
ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells.
Cell Physiol Biochem. 2018; 45(3):917-934 [PubMed] Related Publications
BACKGROUND/AIMS: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood.
METHODS: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatography-mass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry.
RESULTS: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting.
CONCLUSION: TP exerted anti-tumor activity on non-small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP-related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer.

Kim SG, Yooun JH, Kim DE, et al.
A novel anti-cancer agent, FPDHP, induces anoikis in various human cancer cells through activation of calpain, and downregulation of anoikis-related molecules.
J Cell Biochem. 2018; 119(7):5620-5631 [PubMed] Related Publications
Resistance to anoikis and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. Anoikis is a type of apoptosis induced by inadequate cell/extracellular matrix (ECM) attachment and an attractive anti-cancer therapeutic strategy in cancer chemotherapeutic field. Therefore, the development of anoikis-inducing agents is useful and promising to overcome cancer. When FPDHP, a novel anoikis-inducing agent, was treated within 3 h, FPDHP induced massive cell detachment in various human cancer cells, irrespective of apoptosis. Moreover, FPDHP decreased the expression of integrins, FAK, focal adhesion signaling effectors (talin1 and talin2), tight junction proteins (ZO-1, ZO-2, and ZO-3), transcriptional mediators of epithelial-mesenchymal transition (EMT) (Snail1 and Snail2), and anoikis-related protein, such as Mcl-1 (L). Interestingly, Caki/ZO-2 and Caki/α6 are significantly suppressed the FPDHP-mediated cell detachment, and the constitutive active form of Akt and overexpression of Mcl-1 (L) partially inhibited the cellular detachment induced by FPDHP. On the other hand, when FPDHP was treated for more than 12 h, FPDHP induced caspase-dependent apoptosis and release of AIF and cytochrome c from mitochondria. Furthermore, FPDHP down regulated Mcl-1 (L) at post-transcriptional level, and overexpression of Mcl-1 (L) partially attenuated the apoptosis induced by FPDHP. Additionally, PD150606, a calpain inhibitor, attenuated FPDHP-mediated cell detachment and apoptosis. Taken together, these results suggest that FPDHP possesses anoikis-inducing activity or potential making cancer cells susceptible to anoikis, and may be developed as a novel active compound for cancer treatment.

Lin SC, Chu PY, Liao WT, et al.
Glycyrrhizic acid induces human MDA-MB-231 breast cancer cell death and autophagy via the ROS-mitochondrial pathway.
Oncol Rep. 2018; 39(2):703-710 [PubMed] Related Publications
Glycyrrhizic acid (GA), the main component of licorice root extracts, has been shown to suppress cell proliferation and induce apoptosis in various types of cancers. However, the molecular mechanism of its anticancer activity remains poorly understood and warrants further investigation. MDA-MB‑231 cells were treated with various concentrations of GA and the cytotoxic effects of GA were determined using the CCK-8 assay. Apoptosis and cell cycle status were detected by flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (∆Ψm) were assessed using DCFDA, MitoSOX and JC-1 staining. Western blot analysis was used to quantify the expression of autophagy-related proteins. In the present study, induction of autophagic cell death was observed in GA-treated MDA-MB‑231 cells. Downregulation of p62- and beclin 1-associated proteins occurred after GA treatment, and, the conversion of LC3 and increased ROS without significant changes in caspase‑associated proteins and intracellular responses were detected. Furthermore, loss of mitochondria and its membrane potential in cells demonstrated that mitochondria were involved in the GA-regulated MDA-MB-231 cell death. The addition of a pan-caspase inhibitor (z-VAD-fmk) did not suppress the GA-induced apoptotic effect, and GA-induced apoptosis was not accompanied by processing of procaspase-8, -9 and -3. However, GA triggered the translocation of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus. In contrast, GA-induced LC3 conversion was significantly inhibited by 3 methlyadenine (3MA), an inhibitor of PI3K‑regulated autophagy. Therefore, these results suggest that enhancement of both AIF- and LC3-dependent GA-derived ROS generation plays an important role in the inhibition of the growth of MDA-MB-231 human breast cancer cells.

Hammouda MB, Riahi-Chebbi I, Souid S, et al.
Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin.
Biochim Biophys Acta Gen Subj. 2018; 1862(3):600-614 [PubMed] Related Publications
BACKGROUND: The resistance of melanoma cells to cisplatin restricts its clinical use. Therefore, the search for novel tumor inhibitors and effective combination treatments that sensitize tumor cells to this drug are still needed. We purified macrovipecetin, a novel heterodimeric C-type lectin, from Macrovipera lebetina snake venom and investigated its anti-tumoral effect on its own or combined with cisplatin, in human melanoma cells.
METHODS: Biochemical characterization, in vitro cells assays such as viability, apoptosis, adhesion, migration, invasion, Western blotting and in silico analysis were used in this study.
RESULTS: Macrovipecetin decreased melanoma cell viability 100 times more than cisplatin. Interestingly, when combined with the drug, macrovipecetin enhanced the sensitivity of SK-MEL-28 cells by augmenting their apoptosis through increased expression of the apoptosis inducing factor (AIF) and activation of ERK
CONCLUSIONS: We validated the antitumor effect of macrovipecetin when combined, or not, with cisplatin on SK-MEL-28 cells.
GENERAL SIGNIFICANCE: The presented work proposes the potential use of macrovipecetin and cisplatin in combination as an effective anti-melanoma treatment.

Shinderman-Maman E, Cohen K, Moskovich D, et al.
Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer.
Sci Rep. 2017; 7(1):16475 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Ovarian cancer is a highly aggressive disease and novel treatments are required. Thyroid hormones binding to αvβ3 integrin produced growth-promoting activities in ovarian cancer and we hypothesized that natural thyroid hormone derivatives may antagonize these actions. The effect of three antagonists, tetraiodoacetic acid (tetrac), triiodothyroacetic acid (triac) and 3-iodothyronamine (T1AM), on cell proliferation, cell death and DNA damage was studied in two ovarian cancer cell lines (OVCAR3 and A2780), normal hamster ovary control cells (CHOK1) and αvβ3-deficient or transfected HEK293 cells. A differential inhibition of cell proliferation was observed in ovarian cancer cells compared to CHOK1. In OVCAR3, an induction of cell cycle regulators was further shown. Apoptosis was confirmed (annexin-PI, SubG1/cell-cycle, apoptotic genes, caspase-3 and poly ADP ribose polymerase-1 (PARP-1) cleavage) and was reversed by a pan-caspase inhibitor. Induction in apoptosis inducing factor (AIF) was observed, suggesting a parallel caspase-independent mechanism. Integrin-involvement in triac/T1AM apoptotic action was shown in αvβ3-transfected HEK293 cells. Lastly, in ovarian cancer models, key proteins that coordinate recognition of DNA damage, ataxia-telangiectasia mutated (ATM) and PARP-1, were induced. To conclude, the cytotoxic potential of thyroid hormone derivatives, tetrac, triac and T1AM, in ovarian cancer may provide a much-needed novel therapeutic approach.

Mukhopadhyay R, Kazi J, Debnath MC
Synthesis and characterization of copper nanoparticles stabilized with Quisqualis indica extract: Evaluation of its cytotoxicity and apoptosis in B16F10 melanoma cells.
Biomed Pharmacother. 2018; 97:1373-1385 [PubMed] Related Publications
Green synthesis of metallic nanoparticles is a cost-effective environment-friendly technique and Quisqualis indica has ethnomedicinal values. With this background in this study, the floral extract of Q. indica was used to fabricate copper nanoparticles (QCuNPs) from copper acetate. Biophysical analysis revealed the formation of spherical, monodisperse, crystalline QCuNPs. Significant cytotoxic potentials of the nanoformulation were determined by MTT and lactate dehydrogenase (LDH) assay on B16F10 melanoma cells. Estimation of GSH and ROS demonstrated that QCuNPs induced melanoma cell death by induction of oxidative stress. Gene transcript analysis showed up-regulation of caspase-dependent as well as caspase-independent (AIF) apoptotic genes in treated cells. Comparative proteomics study mostly showed the abundance of apoptotic and cell cycle arrest proteins in treated samples. The in vivo therapeutic efficacy was studied in mice bearing B16F10 melanoma tumor where a significant decrease in tumor growth was observed in nanoparticles treated animal model. In conclusion, QCuNPs caused cytotoxicity and apoptosis in melanoma cells and its mechanism was established from gene expression and proteomic studies. QCuNPs exhibited potential suppression of B16F10 melanoma cell proliferation and substantial inhibition of tumor growth in animals. As per our information, this is the first study exploring the potential of Q. indica for the formulation of eco-friendly copper nanoparticle which will have great future application in the medicinal field.

Marx C, Marx-Blümel L, Lindig N, et al.
The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing's sarcoma cell line.
Invest New Drugs. 2018; 36(3):396-406 [PubMed] Related Publications
The sirtuin 1/2 inhibitor tenovin-1 activates p53 and may have potential in the management of cancer. Here, we investigated the responsiveness of Ewing's sarcoma cells to tenovin-1. We examined its effects in two Ewing's sarcoma cell lines with different p53 status, i.e. in p53 wild-type and p53 null cells. Effects were assessed by flow cytometric analyses of cell death, mitochondrial membrane depolarization and reactive oxygen species (ROS) generation, by caspase 3/7 activity measurement, by mRNA expression profiling and by immunoblotting. Tenovin-1 elicited caspase-mediated cell death in p53 wild-type cells, but caspase-independent cell death in p53 null cells. Remarkably, it induced a nonlinear concentration response in the latter: low concentrations of tenovin-1 were much more effective than were higher concentrations. Tenovin-1's effects in p53 null cells involved gene expression changes of Bcl-2 family members, mitochondrial membrane depolarization, nuclear translocation of apoptosis-inducing factor, ROS formation and DNA damage; all these effects followed a bell-shaped pattern. In conclusion, our results provide new insights into tenovin-1's mode of action by demonstrating that it can induce different pathways of cell death.

Wang Y, Xia C, Lun Z, et al.
Crosstalk between p38 MAPK and caspase-9 regulates mitochondria-mediated apoptosis induced by tetra-α-(4-carboxyphenoxy) phthalocyanine zinc photodynamic therapy in LoVo cells.
Oncol Rep. 2018; 39(1):61-70 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Photodynamic therapy (PDT) is considered to be an advancing antitumor technology. PDT using hydrophilic/lipophilic tetra‑α-(4-carboxyphenoxy) phthalocyanine zinc (TαPcZn-PDT) has exhibited antitumor activity in Bel-7402 hepatocellular cancer cells. However, the manner in which p38 MAPK and caspase-9 are involved in the regulation of mitochondria-mediated apoptosis in the TαPcZn-PDT-treated LoVo human colon carcinoma cells remains unclear. Therefore, in the present study, a siRNA targeting p38 MAPK (siRNA-p38 MAPK) and the caspase‑9 specific inhibitor z-LEHD-fmk were used to examine the crosstalk between p38 MAPK and caspase-9 during mitochondria-mediated apoptosis in the TαPcZn-PDT‑treated LoVo cells. The findings revealed that the TαPcZn-PDT treatment of LoVo cells resulted in the induction of apoptosis, the formation of p38 MAPK/caspase-9 complexes, the activation of p38 MAPK, caspase-9, caspase-3 and Bid, the downregulation of Bcl-2, the reduction of mitochondrial membrane potential (ΔΨm), the upregulation of Bax and the release of apoptosis-inducing factor (AIF) and cytochrome c (Cyto c). By contrast, siRNA‑p38 MAPK or z-LEHD-fmk both attenuated the effects of TαPcZn-PDT in the LoVo cells. Furthermore, the results revealed that siRNA-p38 MAPK had more significant inhibitory effects on apoptosis and mitochondria compared with the effects of z-LEHD-fmk in TαPcZn-PDT-treated LoVo cells. These findings indicated that p38 MAPK plays the major regulatory role in the crosstalk between p38 MAPK and caspase-9 and that direct interaction between p38 MAPK and caspase-9 may regulate mitochondria-mediated apoptosis in the TαPcZn-PDT-treated LoVo cells.

Shih YL, Hung FM, Lee CH, et al.
Fisetin Induces Apoptosis of HSC3 Human Oral Cancer Cells Through Endoplasmic Reticulum Stress and Dysfunction of Mitochondria-mediated Signaling Pathways.
In Vivo. 2017 Nov-Dec; 31(6):1103-1114 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND/AIM: Oral cancer has been reported to be one of the major cancer-related diseases in human populations and the treatment of oral cancer is still unsatisfied. Fisetin, is a flavonoid from plants and has several biological activities such as antioxidant, anti-inflammatory and anticancer function, but its cytotoxicity in human oral cancer cells is unknown. In the present study, we investigated fisetin-induced cytotoxic effects on HSC3 human oral cancer cells in vitro. Materials and Methods/Results: We used flow cytometric assay to show fisetin induced apoptotic cell death through increased reactive oxygen species and Ca
CONCLUSION: Based on these observations, we suggest that fisetin induces apoptotic cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.

Maiuthed A, Pinkhien T, Chamni S, et al.
Apoptosis-inducing Effect of Hydroquinone 5-
Anticancer Res. 2017; 37(11):6259-6267 [PubMed] Related Publications
BACKGROUND: A newly-synthesized derivative of renieramycin M (RM), an anticancer lead compound isolated from the blue sponge Xestospongia sp., hydroquinone 5-O-cinnamoyl ester (CIN-RM), was investigated here for its activity against non-small cell lung cancer cells.
MATERIALS AND METHODS: Cytotoxicity effects of CIN-RM and RM on H292 lung cancer cells were determined by the MTT assay. We also investigated the mechanism of CIN-RM-mediated apoptosis and mechanism of action of this compound by western blotting.
RESULTS: CIN-RM showed more potent cytotoxicity than its parental compound (RM) against H292 lung cancer cells. At concentrations of 15-60 μM, CIN-RM significantly induced apoptosis by increasing expression of apoptosis-inducing factor (AIF) and activation of caspase-3 and -9. For up-stream mechanism, CIN-RM mediated apoptosis through a p53-dependent mechanism, that consequently down-regulated anti-apoptotic B-cell lymphoma 2 (BCL2), while increasing the level of pro-apoptotic BCL2-associated X (BAX). In addition, phosphorylation of pro-survival protein AKT was found to be dramatically reduced.
CONCLUSION: This study revealed the potential of CIN-RM for apoptosis induction and in the development of a novel anticancer agent.

Wang Y, Chen K, Cai Y, et al.
Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma.
J Exp Clin Cancer Res. 2017; 36(1):111 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance.
METHODS: We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo.
RESULTS: First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2) using shRNA, we demonstrate enhanced drug sensitivity for doxorubicin (2.77-fold) and etoposide (7.87-fold) compared with control. Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo.
CONCLUSION: Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.

Park YH, Seo JH, Park JH, et al.
Hsp70 acetylation prevents caspase-dependent/independent apoptosis and autophagic cell death in cancer cells.
Int J Oncol. 2017; 51(2):573-578 [PubMed] Related Publications
Cancer cells are continuously challenged by adverse environmental factors including hypoxia, metabolite restriction, and immune reactions, and must adopt diverse strategies to survive. Heat shock protein (Hsp) 70 plays a central role in protection against stress-induced cell death by maintaining protein homeostasis and interfering with the process of programmed cell death. Recent findings have suggested that Hsp70 acetylation is a key regulatory modification required for its chaperone activity, but its relevance in the process of programmed cell death and the underlying mechanisms involved are not well understood. In this study, we sought to investigate mechanisms mediated by Hsp70 acetylation in relation to apoptotic and autophagic programmed cell death. Upon stress-induced apoptosis, Hsp70 acetylation inhibits apoptotic cell death, mediated by Hsp70 association with apoptotic protease-activating factor (Apaf)-1 and apoptosis-inducing factor (AIF), key modulators of caspase-dependent and -independent apoptotic pathways, respectively. Hsp70 acetylation also attenuated autophagic cell death associated with upregulation of autophagy-related genes and autophagosome induction. Collectively, these results suggest that the acetylation of Hsp70 plays key regulatory roles in cell death pathways as well as in its function as a chaperone, together enabling cellular protection in response to stress.

Maioral MF, Bodack CDN, Stefanes NM, et al.
Cytotoxic effect of a novel naphthylchalcone against multiple cancer cells focusing on hematologic malignancies.
Biochimie. 2017; 140:48-57 [PubMed] Related Publications
Chalcones are natural compounds described in the literature by its several properties including cytotoxic activity against several tumor types. Considering that the search for new chemotherapeutic agents is still necessary, the aim of this study was to investigate the cytotoxic mechanisms involved in cell death induced by a synthetic chalcone (A23) on different tumor cells. Chalcone A23 reduced the cell viability of twelve tumor cell lines in a concentration and time dependent manner and it was more cytotoxic against acute leukemia cells. Interestingly, the compound was non cytotoxic to normal cells and non-hemolytic to normal red blood cells. Chalcone A23 decreased the expression of cell proliferation marker KI-67 and blocked the G2/M phase in both K562 and Jurkat cell lines. Cells treated with A23 showed morphological features suggestive of apoptosis, the "latter pattern" in agarose gel, the externalization of phosphatidylserine and caspase-3 and PARP cleavage. Chalcone A23 significantly reduced the mitochondrial membrane potential, decreased the expression of anti-apoptotic proteins Bcl-2 and survivin and increased the expression of pro-apoptotic protein Bax, confirming the involvement of the intrinsic pathway. The increased mitochondrial permeability resulted in the release of AIF, cytochrome c and endonuclease G from the mitochondria to the cytosol. In addition, chalcone A23 increased the expression of FasR and induced Bid cleavage, showing the involvement of the extrinsic pathway. Finally, chalcone A23 seems to have a synergic effect with the chemotherapy drugs cytarabine and vincristine. These results suggest that A23 is an interesting compound with strong and selective anti-tumor activity.

Mbuthia KS, Mireji PO, Ngure RM, et al.
Tea (Camellia sinensis) infusions ameliorate cancer in 4TI metastatic breast cancer model.
BMC Complement Altern Med. 2017; 17(1):202 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Tea (Camellia sinensis) infusions are widely consumed beverages with numerous health benefits. However, physiological and molecular responses mediating these activities are poorly understood.
METHOD: Three replicates of 4TI cancer cell suspension (2.0 × 10
RESULTS: Green tea had the highest inhibition on 4TI cells proliferation at a concentration of IC
CONCLUSION: These findings on caspases offer valuable information on the mechanism of tea as an anticancer agent and will contribute to further research in future novel treatments.

Zheng HC, Liu JJ, Li J, et al.
The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.
Oncotarget. 2017; 8(14):23603-23612 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc, Cyclin D1, mTOR, and Raptor. According to transcriptomic analysis, WT parafibromin suppressed PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.

Liu KC, Shih TY, Kuo CL, et al.
Sulforaphane Induces Cell Death Through G2/M Phase Arrest and Triggers Apoptosis in HCT 116 Human Colon Cancer Cells.
Am J Chin Med. 2016; 44(6):1289-1310 [PubMed] Related Publications
Sulforaphane (SFN), an isothiocyanate, exists exclusively in cruciferous vegetables, and has been shown to possess potent antitumor and chemopreventive activity. However, there is no available information that shows SFN affecting human colon cancer HCT 116 cells. In the present study, we found that SFN induced cell morphological changes, which were photographed by contrast-phase microscopy, and decreased viability. SFN also induced G2/M phase arrest and cell apoptosis in HCT 116 cells, which were measured with flow cytometric assays. Western blotting indicated that SFN increased Cyclin A, cdk 2, Cyclin B and WEE1, but decreased Cdc 25C, cdk1 protein expressions that led to G2/M phase arrest. Apoptotic cell death was also confirmed by Annexin V/PI and DAPI staining and DNA gel electrophoresis in HCT 116 cells after exposure to SFN. The flow cytometric assay also showed that SFN induced the generation of reactive oxygen species (ROS) and Ca[Formula: see text] and decreased mitochondria membrane potential and increased caspase-8, -9 and -3 activities in HCT 116 cell. Western blotting also showed that SFN induced the release of cytochrome c, and AIF, which was confirmed by confocal microscopy examination. SFN induced ER stress-associated protein expression. Based on those observations, we suggest that SFN may be used as a novel anticancer agent for the treatment of human colon cancer in the future.

Xiong Z, Guo M, Yu Y, et al.
Downregulation of AIF by HIF-1 contributes to hypoxia-induced epithelial-mesenchymal transition of colon cancer.
Carcinogenesis. 2016; 37(11):1079-1088 [PubMed] Related Publications
Recently, we have reported that apoptosis-inducing factor (AIF) regulates the epithelial-mesenchymal transition (EMT) process of cancers, but the mechanisms underlying the regulation of AIF expression in cancers remain greatly unknown. Here, we report that hypoxia inversely correlates with the expression of AIF in tumor tissues from a cohort of colon cancer patients and inhibits AIF expression in multiple colon cancer cell lines. This inhibition is mediated by hypoxia-inducible factor-1 (HIF-1), which transcriptionally represses AIF through direct binding to the hypoxia-response element in AIF promoter as revealed by luciferase reporter and chromatin immunoprecipitation assays. We also show that downregulation of AIF contributes to hypoxia-induced EMT as overexpression or silencing of AIF partially reverses or potentiates the EMT program initiated by hypoxic treatment. Mechanistic study reveals that downregulation of AIF by hypoxia causes oxidative inactivation of the lipid phosphatase activity of phosphatase and tensin homolog on chromosome 10 (PTEN), with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3β and activation of WNT/β-catenin signaling in colon cancer cells. These results identify AIF as a novel target gene of HIF-1 and reveal the role of AIF downregulation in hypoxia-induced EMT.

Jagadish N, Gupta N, Agarwal S, et al.
Sperm-associated antigen 9 (SPAG9) promotes the survival and tumor growth of triple-negative breast cancer cells.
Tumour Biol. 2016; 37(10):13101-13110 [PubMed] Related Publications
Recently, we demonstrated the association of sperm-associated antigen 9 (SPAG9) expression with breast cancer. Among breast cancer, 15 % of the cancers are diagnosed as triple-negative breast cancers (TNBC) based on hormone receptor status and represent an important clinical challenge because of lack of effective available targeted therapy. Therefore, in the present investigation, plasmid-based small hairpin (small hairpin RNA (shRNA)) approach was used to ablate SPAG9 in aggressive breast cancer cell line model (MDA-MB-231) in order to understand the role of SPAG9 at molecular level in apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT) signaling. Our data in MDA-MB-231 cells showed that ablation of SPAG9 resulted in membrane blebbing, increased mitochondrial membrane potential, DNA fragmentation, phosphatidyl serine surface expression, and caspase activation. SPAG9 depletion also resulted in cell cycle arrest in G0-G1 phase and induced cellular senescence. In addition, in in vitro and in vivo xenograft studies, ablation of SPAG9 resulted in upregulation of p21 along with pro-apoptotic molecules such as BAK, BAX, BIM, BID, NOXA, AIF, Cyto-C, PARP1, APAF1, Caspase 3, and Caspase 9 and epithelial marker, E-cadherin. Also, SPAG9-depleted cells showed downregulation of cyclin B1, cyclin D1, cyclin E, CDK1, CDK4, CDK6, BCL2, Bcl-xL, XIAP, cIAP2, MCL1, GRP78, SLUG, SNAIL, TWIST, vimentin, N-cadherin, MMP2, MMP3, MMP9, SMA, and β-catenin. Collectively, our data suggests that SPAG9 promotes tumor growth by inhibiting apoptosis, altering cell cycle, and enhancing EMT signaling in in vitro cells and in vivo mouse model. Hence, SPAG9 may be a potential novel target for therapeutic use in TNBC treatment.

Li X, Zhang G, Chen Q, et al.
CD317 Promotes the survival of cancer cells through apoptosis-inducing factor.
J Exp Clin Cancer Res. 2016; 35(1):117 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Low nutrient environment is a major obstacle to solid tumor growth. However, many tumors have developed adaptive mechanisms to circumvent the requirement for exogenous growth factors.
METHODS: Here we used siRNA interference or plasmid transfection techniques to knockdown or enhance CD317 expression respectively, in mammalian cancer cells, and subjected these CD317-manipulated cells to serum deprivation to study the role of CD317 on stress-induced apoptosis and the underlying mechanism.
RESULTS: We report that CD317, an innate immune gene overexpressed in human cancers, protected cancer cells against serum deprivation-induced apoptosis. In tumor cells, loss of CD317 markedly enhanced their susceptibility to serum deprivation-induced apoptosis with no effect on autophagy or caspase activation, indicating an autophagy- and caspase-independent mechanism of CD317 function. Importantly, CD317 knockdown in serum-deprived tumor cells impaired mitochondria function and subsequently promoted apoptosis-inducing factor (AIF) release and nuclear translocation but had little effect on mitochondrial and cytoplasmic distributions of cytochrome C, a pro-apoptotic factor released from mitochondria that initiates caspase processing in response to death stimuli. Furthermore, overexpression of CD317 in HEK293T cells inhibits serum deprivation-induced apoptosis as well as the release and nuclear accumulation of AIF.
CONCLUSION: Our data suggest that CD317 functions as an anti-apoptotic factor through the mitochondria-AIF axis in malnourished condition and may serve as a potential drug target for cancer therapy.

Zhao S, Yang XF, Shen DF, et al.
The down-regulated ING5 expression in lung cancer: a potential target of gene therapy.
Oncotarget. 2016; 7(34):54596-54615 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
ING5 can interact with p53, thereby inhibiting cell growth and inducing apoptosis. We found that ING5 overexpression not only inhibited proliferation, migration, and invasion, but also induced G2 arrest, differentiation, autophagy, apoptosis, glycolysis and mitochondrial respiration in lung cancer cells. ING5 transfection up-regulated the expression of Cdc2, ATG13, ATG14, Beclin-1, LC-3B, AIF, cytochrome c, Akt1/2/3, ADFP, PFK-1 and PDPc, while down-regulated the expression of Bcl-2, XIAP, survivin,β-catenin and HXK1. ING5 transfection desensitized cells to the chemotherapy of MG132, paclitaxel, and SAHA, which paralleled with apoptotic alteration. ING5 overexpression suppressed the xenograft tumor growth by inhibiting proliferation and inducing apoptosis. ING5 expression level was significantly higher in normal tissue than that in lung cancer at both protein and mRNA levels. Nuclear ING5 expression was positively correlated with ki-67 expression and cytoplasmic ING5 expression. Cytoplasmic ING5 expression was positively associated with lymph node metastasis, and negatively with age, lymphatic invasion or CPP32 expression. ING5 expression was different in histological classification: squamous cell carcinoma > adenocarcinoma > large cell carcinoma > small cell carcinoma. Taken together, our data suggested that ING5 downregulation might involved in carcinogenesis, growth, and invasion of lung cancer and could be considered as a promising marker to gauge the aggressiveness of lung cancer. It might be employed as a potential target for gene therapy of lung cancer.

Bhoopathi P, Lee N, Pradhan AK, et al.
mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM.
Cancer Res. 2016; 76(12):3572-82 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Advanced stages of neuroblastoma, the most common extracranial malignant solid tumor of the central nervous system in infants and children, are refractive to therapy. Ectopic expression of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) promotes broad-spectrum antitumor activity in vitro, in vivo in preclinical animal models, and in a phase I clinical trial in patients with advanced cancers without harming normal cells. mda-7/IL-24 exerts cancer-specific toxicity (apoptosis or toxic autophagy) by promoting endoplasmic reticulum stress and modulating multiple signal transduction pathways regulating cancer cell growth, invasion, metastasis, survival, and angiogenesis. To enhance cancer-selective expression and targeted anticancer activity of mda-7/IL-24, we created a tropism-modified cancer terminator virus (Ad.5/3-CTV), which selectively replicates in cancer cells producing robust expression of mda-7/IL-24 We now show that Ad.5/3-CTV induces profound neuroblastoma antiproliferative activity and apoptosis in a caspase-3/9-independent manner, both in vitro and in vivo in a tumor xenograft model. Ad.5/3-CTV promotes these effects through a unique pathway involving apoptosis-inducing factor (AIF) translocation into the nucleus. Inhibiting AIF rescued neuroblastoma cells from Ad.5/3-CTV-induced cell death, whereas pan-caspase inhibition failed to promote survival. Ad.5/3-CTV infection of neuroblastoma cells increased ATM phosphorylation instigating nuclear translocation and increased γ-H2AX, triggering nuclear translocation and intensified expression of AIF. These results were validated further using two ATM small-molecule inhibitors that attenuated PARP cleavage by inhibiting γ-H2AX, which in turn inhibited AIF changes in Ad.5/3-CTV-infected neuroblastoma cells. Taken together, we elucidate a novel pathway for mda-7/IL-24-induced caspase-independent apoptosis in neuroblastoma cells mediated through modulation of AIF, ATM, and γ-H2AX. Cancer Res; 76(12); 3572-82. ©2016 AACR.

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