Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

Kaufmann, Scott H.; Vaux, David L.

doi:10.1038/sj.onc.1206945

Cited by 249 publications

(194 citation statements)

References 224 publications

Supporting

Mentioning

188

Contrasting

Unclassified

Order By: Relevance

“…3,4 Virtually all known apoptosis signal pathways converge on the caspases. 5 The inhibitor of apoptosis (IAP) genes encode a family of proteins that bind and inactivate key caspases involved in the initiation (Caspase-9) and execution (Caspase-3 and -7) of this cascade. 6 An elevated expression level of XIAP, the most potent of the mammalian IAPs, is associated with tumor resistance to cell death cues.…”

Section: Uiccmentioning

confidence: 99%

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

Liston

Cui

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

XAF1 (XIAP-associated factor 1) is a novel XIAP binding protein that can antagonize XIAP and sensitize cells to other cell death triggers. Our previous results have shown that aberrant hypermethylation of the CpG sites in XAF1 promoter is strongly associated with lower expression of XAF1 in gastric cancers. In our study, we investigated the effect of restoration of XAF1 expression on growth of gastric cancers. We found that the restoration of XAF1 expression suppressed anchorage-dependent and -independent growth and increased sensitivity to TRAIL and druginduced apoptosis. Stable cell clones expressing XAF1 exhibited delayed tumor initiation in nude mice. Restoration of XAF1 expression mediated by adenovirus vector greatly increased apoptosis in gastric cancer cell lines in a time-and dose-dependent manner and sensitized cancer cells to TRAIL and drugs-induced apoptosis. Adeno-XAF1 transduction induced cell cycle G2/M arrest and upregulated the expression of p21 and downregulated the expression of cyclin B1 and cdc2. Notably, adeno-XAF1 treatment significantly inhibited tumor growth, strongly enhanced the antitumor activity of TRAIL in a gastric cancer xenograft model in vivo, and significantly prolonged the survival time of animals bearing tumor xenografts. Complete eradication of established tumors was achieved on combined treatment with adeno-XAF1 and TRAIL. Our results document that the restoration of XAF1 inhibits gastric tumorigenesis and tumor growth and that XAF1 is a promising candidate for cancer gene therapy. ' UICCKey words: XAF1; TRAIL; adenovirus; apoptosis; tumorigenesis; cell cycle arrest; gastric cancer; gene therapy The development of cancer is a result of aberrant cellular proliferation and failure of these cells to undergo apoptosis in response to normal signaling cues. 1 Dysregulation of cell death pathways has been termed a 'hallmarkÕ of cancer 2 and is required for tumor initiation, progression and drug resistance. 3,4 Virtually all known apoptosis signal pathways converge on the caspases. 5 The inhibitor of apoptosis (IAP) genes encode a family of proteins that bind and inactivate key caspases involved in the initiation (Caspase-9) and execution (Caspase-3 and -7) of this cascade. 6 An elevated expression level of XIAP, the most potent of the mammalian IAPs, is associated with tumor resistance to cell death cues. 7,8 Thus the strategies that target XIAP synthesis or function are under investigation for the treatment of cancer. 9 Both antisense 10,11 and small molecule inhibitors of XIAP function 12,13 have demonstrated promise in animal models of human cancer.XAF1 has been previously identified as a XIAP binding partner. 13 XAF1 directly interacts with endogenous XIAP and results in XIAP sequestration in nuclear inclusions. XAF1 antagonizes the anticaspase activity of XIAP and reverses the protective effect of XIAP overexpression in cell lines. 13 XAF1 does not contain an amino terminal tetrapeptide motif analogous to Smac/DIABLO or Omi, suggesting that its mechanism of IAP interaction ...

show abstract

Section: Uiccmentioning

confidence: 99%

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

Liston

Cui

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…In fact, genetic alterations of BCL-2 family members have been described in various human cancers, such as follicular lymphoma, breast cancer, colorectal cancer or melanoma. 9 The expression of BCL-2 proteins correlates with prognosis in some studies of non-small-cell-lung cancer (NSCLC) patients. 10 In contrast, loss of caspase-9 or the adapter Apaf-1 failed to accelerate Myc-induced lymphomagenesis in mice, 11 and inactivating mutations or loss of expression of these factors are rarely observed in human cancers.…”

mentioning

confidence: 99%

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

et al. 2007

View full text Add to dashboard Cite

During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and -3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.

show abstract

“…The importance of BCL-2 activity in promoting evasion of apoptosis by cancer cells has been well established in preclinical tumor models and has supported the initiation of clinical trials focused on blocking the activity or expression of BCL-2 in certain cancers (2). Although not as frequent, direct impairment of death receptor dependent apoptosis via mutations and down-regulation of DISC components has also been observed (13,14).…”

mentioning

confidence: 99%

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Dompe

Rivers

Li³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.

show abstract

Alterations in the apoptotic machinery and their potential role in anticancer drug resistance

Cited by 249 publications

References 224 publications

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer

A whole-genome RNAi screen identifies an 8q22 gene cluster that inhibits death receptor-mediated apoptosis

Contact Info

Product

Resources

About