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.

SIRT1 in the Development and Treatment of Hepatocellular Carcinoma

“…tNOX converts reduced NADH to oxidized NAD. Importantly, tNOX inhibition reduces intracellular NAD concentration, which influences SIRT1 function (241, 243, 244). Suppression of tNOX by a multitude of agents activated apoptosis and diminished malignant cell growth (244, 245).…”

Screening of molecular targets and construction of a ceRNA network for oxaliplatin resistance in colorectal cancer

“…This prevents the separation of DNA strands during transcription and translation, inducing cancer cell apoptosis. [5][6][7][8] Cancer cells can develop resistance to oxaliplatin. Oxaliplatin resistance can be divided into two categories: congenital drug resistance and acquired drug resistance.…”

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

“…Similar findings by another study [41] clearly suggest that tNOX-oxaliplatin binding interferes with its oxidase activity and plays a critical role in regulating apoptosis. Using in vitro cell models, we confirmed that tNOX depletion restored non-cancer phenotypes, including abrogated anchorage-independent growth, increased sensitivity to stress-mediated apoptosis, attenuated migration, and prolonged cell cycle progression, further supporting the importance of tNOX in cancer management [17,19,21,25,42].…”

“…Overexpression of tNOX in non-cancer cells and its depletion in cancer cells confirmed that tNOX is essential for and positively associated with cell proliferation and migration [17,18,19,20,21]. In cancer therapy, it is thought that the suppression of tNOX by various agents (e.g., capsaicin, epigallocatechin gallate, tamoxifen, oxaliplatin) induces apoptosis and attenuates cancer cell growth [19,22,23,24,25]. tNOX converts reduced NADH or hydroquinones to oxidized NAD + [14,15,26], and recent studies have demonstrated that inhibition of tNOX activity reduces the intracellular NAD + level, which in turn impacts NAD + -dependent SIRT1 deacetylase activity and apoptosis [8,25,27].…”