title: Tumor-associated NADH oxidase (tNOX)-NAD+-sirtuin 1 axis contributes to oxaliplatin-induced apoptosis of gastric cancer cells.
abstract: Oxaliplatin belongs to the platinum-based drug family and has shown promise in cancer treatment. The major mechanism of action of platinum compounds is to form platinum-DNA adducts, leading to DNA damage and apoptosis. Accumulating evidence suggests that they might also target non-DNA molecules for their apoptotic activity. We explored the effects of oxaliplatin on a tumor-associated NADH oxidase (tNOX) in gastric cancer lines. In AGS cells, we found that the oxaliplatin-inhibited tNOX effectively attenuated the NAD+/NADH ratio and reduced the deacetylase activity of an NAD+-dependent sirtuin 1, thereby enhancing p53 acetylation and apoptosis. Similar results were also observed in tNOX-knockdown AGS cells. In the more aggressive MKN45 and TMK-1 lines, oxaliplatin did not inhibit tNOX, and induced only minimal apoptosis and cytotoxicity. However, the downregulation of either sirtuin 1 or tNOX sensitized TMK-1 cells to oxaliplatin-induced apoptosis. Moreover, tNOX-depletion in these resistant cells enhanced spontaneous apoptosis, reduced cyclin D expression and prolonged the cell cycle, resulting in diminished cancer cell growth. Together, our results demonstrate that oxaliplatin targets tNOX and SIRT1, and that the tNOX-NAD+-sirtuin 1 axis is essential for oxaliplatin-induced apoptosis.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
authors.forename: Huei-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.|Department of Surgery, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan.
authors.forename: Tien-Ming
authors.initials: TM
authors.lastname: Yuan
authors.affiliation: Department of Surgery, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan.
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.
authors.forename: You-Yu
authors.initials: YY
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan.|Graduate Institute of Basic Medicine, China Medical University, Taichung, 40402, Taiwan.|Department of Medical Research, China Medical University Hospital, Taichung, 40402, Taiwan.|Department of Biotechnology, Asia University, Taichung, 41354, Taiwan.
authors.forename: Pin Ju
authors.initials: PJ
authors.lastname: Chueh
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009243:NAD / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D009243:NAD; D009247:NADH, NADPH Oxidoreductases; C431909:tumor-associated NADH oxidase; D056564:Sirtuin 1
keywords: apoptosis; deacetylase; oxaliplatin; sirtuin 1 (SIRT1); tumor-associated NADH oxidase (tNOX or ENOX2)