Abstract 4770: TNFα and IFN-γ cooperate to up-regulate Fas expression to sensitize human colon carcinoma cells to Fas mediated apoptosis

Abstract

Abstract Fas (also known as CD95) is a member of the tumor necrosis factor (TNF) superfamily that mediates the extrinsic apoptosis signaling pathway when engaged by its physiological ligand FasL. Although the Fas death receptor has been shown to initiate cellular proliferation and survival signal pathways in certain tumor cells uder certain conditions, it is generally believed that under physiological conditions Fas functions as a guardian against not only autoimmunity but also other disease including cancer. Fas is highly expressed in normal human colon epithelial cells but is often down-regulated in human colorectal carcinoma, whereas complete loss of Fas expression is often observed in metastatic human colorectal carcinoma. These observations thus suggest that colon carcinoma cells might use loss of Fas expression and/or function to acquire an apoptosis resistant phenotype to advance the disease. Therefore, re-activating Fas expression might be an effective approach to sensitize the human colon carcinoma cells to apoptosis to suppress tumor development. In this study, we demonstrated that there exist CpG islands in the human Fas promoter region and inhibition of DNA methylation up-regulates Fas expression in metastatic human colon carcinoma cells, resulting in increased tumor cell sensitivity to Fas-mediated apoptosis. However, bisulfite DNA sequencing revealed that there are just a few methylated CpGs in the human Fas promoter region in metastatic human colon carcinoma cells, suggesting that DNA methylation mediates Fas expression indirectly. On the other hand, TNFα and IFN-γ, when used in combination, dramatically up-regulated Fas expression level in the metastatic human colon carcinoma cells. Up-regulation of Fas by TNFα and IFN-γ also resulted in sensitization of the metastatic colon carcinoma cells to Fas-mediated apoptosis. Our data thus suggest that re-activation of the death receptor Fas might be an effective approach to enhance the efficacy of Fas-based therapy against metastatic human colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4770. doi:10.1158/1538-7445.AM2011-4770