title: Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo.
abstract: The death receptor Fas and its physiological ligand (FasL) regulate apoptosis of cancerous cells, thereby functioning as a critical component of the host cancer immunosurveillance system. To evade Fas-mediated apoptosis, cancer cells often downregulate Fas to acquire an apoptosis-resistant phenotype, which is a hallmark of metastatic human colorectal cancer. Therefore, targeting Fas resistance is of critical importance in Fas-based cancer therapy and immunotherapy. In this study, we demonstrated that epigenetic inhibitors decitabine and vorinostat cooperate to upregulate Fas expression in metastatic human colon carcinoma cells. Decitabine also upregulates BNIP3 and Bik expression, whereas vorinostat decreased Bcl-x(L) expression. Altered expression of Fas, BNIP3, Bik, and Bcl-x(L) resulted in effective sensitization of the metastatic human colon carcinoma cells to FasL-induced apoptosis. Using an experimental metastasis mouse model, we further demonstrated that decitabine and vorinostat cooperate to suppress colon carcinoma metastasis. Analysis of tumor-bearing lung tissues revealed that a large portion of tumor-infiltrating CD8(+) T cells are FasL(+), and decitabine and vorinostat-mediated tumor-suppression efficacy was significantly decreased in Fas(gld) mice compared with wild-type mice, suggesting a critical role for FasL in decitabine and vorinostat-mediated tumor suppression in vivo. Consistent with their function in apoptosis sensitization, decitabine and vorinostat significantly increased the efficacy of CTL adoptive transfer immunotherapy in an experimental metastasis mouse model. Thus, our data suggest that combined modalities of chemotherapy to sensitize the tumor cell to Fas-mediated apoptosis and CTL immunotherapy is an effective approach for the suppression of colon cancer metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Dafeng
authors.initials: D
authors.lastname: Yang
authors.forename: Christina M
authors.initials: CM
authors.lastname: Torres
authors.forename: Kankana
authors.initials: K
authors.lastname: Bardhan
authors.forename: Mary
authors.initials: M
authors.lastname: Zimmerman
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000077209:Decitabine; D053222:Fas Ligand Protein / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D024101:Mitochondrial Proteins / Q000276:immunology; D009362:Neoplasm Metastasis / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology; D000077337:Vorinostat; D051020:bcl-X Protein / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C096820:BIK protein, human; C090121:BNIP3 protein, human; C508686:BNip3 protein, mouse; C494812:Bcl2l1 protein, mouse; C111741:Bik protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine