Oncotarget

Research Papers:

Tumor-associated NADH oxidase (tNOX)-NAD+-sirtuin 1 axis contributes to oxaliplatin-induced apoptosis of gastric cancer cells

Huei-Yu Chen, Hsiao-Ling Cheng, Yi-Hui Lee, Tien-Ming Yuan, Shi-Wen Chen, You-Yu Lin and Pin Ju Chueh _

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Oncotarget. 2017; 8:15338-15348. https://doi.org/10.18632/oncotarget.14787

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Abstract

Huei-Yu Chen1, Hsiao-Ling Cheng1, Yi-Hui Lee1, Tien-Ming Yuan1,2, Shi-Wen Chen2, You-Yu Lin1, Pin Ju Chueh1,3,4,5

1Institute of Biomedical Sciences, National Chung Hsing University, Taichung, 40227, Taiwan

2Department of Surgery, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung 42055, Taiwan

3Graduate Institute of Basic Medicine, China Medical University, Taichung, 40402, Taiwan

4Department of Medical Research, China Medical University Hospital, Taichung, 40402, Taiwan

5Department of Biotechnology, Asia University, Taichung, 41354, Taiwan

Correspondence to:

Pin Ju Chueh, email: [email protected]

Keywords: apoptosis, deacetylase, oxaliplatin, tumor-associated NADH oxidase (tNOX or ENOX2), sirtuin 1 (SIRT1)

Received: October 20, 2016     Accepted: January 09, 2017     Published: January 21, 2017

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.


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