Overcoming Resistance to Interferon-Induced Apoptosis of Renal Carcinoma and Melanoma Cells by DNA Demethylation

Reu, Frederic J.; Bae, Sohyun; Cherkassky, Leonid; Leaman, Douglas W.; Lindner, Daniel J.; Beaulieu, Normand; MacLeod, A. Robert; Borden, Ernest C.

doi:10.1200/jco.2005.03.4074

Cited by 115 publications

(108 citation statements)

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“…17,[31][32][33][34] Epigenetic silencing of the XAF1 gene by aberrant promoter methylation appears to correlate with the malignant progression of human gastric tumors. 18,33 In our study, we demonstrate that overexpression of XAF1 suppressed anchorage-dependent and -independent growth.…”

Section: Discussionmentioning

confidence: 99%

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

Liston

Cui

et al. 2009

Intl Journal of Cancer

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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 ...

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Section: Discussionmentioning

confidence: 99%

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

Liston

Cui

et al. 2009

Intl Journal of Cancer

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“…XAF1 interacts with an inhibitor of apoptosis (XIAP) that may function as a competitive inhibitor of caspases to play a critical role in TRAIL-induced apoptosis (Deveraux et al, 1997;Liston et al, 2001;Leaman et al, 2002;Chawla-Sarkar et al, 2004). XAF1 has been silenced by DNA methylation in gastric cancer and is frequently reduced in expression in melanoma (Byun et al, 2003;Ng et al, 2004;Reu et al, 2006a). However, in SK-MEL-3 and SK-MEL-28 cells, 5-AZAdC had a marginal effect on XAF1 mRNA expression (Table 1).…”

Section: Role Of Trail In Sensitization To Ifns By 5-azadcmentioning

confidence: 99%

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL

et al. 2007

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Human melanoma cell lines, SK-MEL-3 and SK-MEL-28, despite induction of the proapoptotic cytokine, Apo2L/TRAIL, did not undergo apoptosis in response to interferons . Postulating that genes important for apoptosis induction by IFNs might be silenced by methylation, the DNA demethylating agent 5-aza-2 0 -deoxycytidine (5-AZAdC) was assessed. DR4 (TRAIL-R1) was identified as one of the genes reactivated by 5-AZAdC with a >3-fold increase in 8 of 10 melanoma cell lines. Pretreatment with 5-AZAdC sensitized SK-MEL-3 and SK-MEL-28 cells to apoptosis induced by IFN-a2b and IFN-b; methylation-specific PCR and bisulfite sequencing confirmed demethylation of 5 0 CpG islands of DR4 and flow cytometry showed an increase in DR4 protein on the cell surface. In cells with reactivated DR4, neutralizing mAB to TRAIL reduced apoptosis in response to IFN-b or Apo2L/TRAIL. To further confirm the role of DR4, it was expressed by retroviral vector in SK-MEL-3 and SK-MEL-28 cells with reversal of resistance to IFN-b and Apo2L/TRAIL. Thus, reexpressing DR4 by 5-AZAdC or retroviral transfection in melanoma cell in which promoter methylation had suppressed its expression, potentiated apoptosis by IFNa2b, IFN-b and Apo2L/TRAIL. Reactivation of silenced proapoptotic genes by inhibitors of DNA methylation may enhance clinical response to IFNs or Apo2L/TRAIL.

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“…Silencing of genes involved in signaling downstream of interferon, such as interferon regulatory factor 8 and XIAPassociated factor 1 trigger resistance of tumor cells to interferon therapy (Reu et al, 2006;Yang et al, 2007). However, injection of decitabine in nude mice carrying melanoma xenografts led to resensitization to interferon treatment (Reu et al, 2006). A phase I clinical trial of decitabine together with interleukin-2 in melanoma patients further showed an objective response in 31% of the patients (Gollob et al, 2006).…”

Section: Epigenetic Cancer Therapymentioning

confidence: 99%

“…In melanoma, for instance, one of the standard treatments is interferon, which induces tumor apoptosis, differentiation and increases the anti-tumor immune response. Silencing of genes involved in signaling downstream of interferon, such as interferon regulatory factor 8 and XIAPassociated factor 1 trigger resistance of tumor cells to interferon therapy (Reu et al, 2006;Yang et al, 2007). However, injection of decitabine in nude mice carrying melanoma xenografts led to resensitization to interferon treatment (Reu et al, 2006).…”

Section: Epigenetic Cancer Therapymentioning

confidence: 99%

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

2010

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An important feature of cancer is dysregulation of gene activity and gene expression, which is driven by a combination of acquired genetic and epigenetic alterations. Here, we will highlight how insights into the epigenetic processes underpinning tumor biology have led to the emerging field of cancer pharmaco-epigenomics. First, we will discuss how interference with the epigenetic machinery in cancer is leading to novel promising therapies, with several DNA methyltransferase and histone deacetylase inhibitors being approved for cancer treatment. Second, we will discuss how epigenetic markers in cancer may increasingly be used as complementary diagnostic tools, prognostic markers of disease progression, and predictive markers of treatment response. Although the anti-tumoral activities of epigenetic therapies have thus far been attributed to reactivation of silenced tumor-suppressor and/or apoptotic genes, they may also influence the tumor environment by directly affecting stromal cells. As an example, we will discuss how tumor-endothelial cells are regulated at the epigenetic level and are affected by methyltransferase and histone deacetylase inhibitors.

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Overcoming Resistance to Interferon-Induced Apoptosis of Renal Carcinoma and Melanoma Cells by DNA Demethylation

Cited by 115 publications

References 45 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

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL

Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy

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