Abstract 1127: Small molecule SIRT3 inhibitor 4′-bromo-resveratrol inhibits proliferation, promotes apoptosis and causes metabolic reprograming of human melanoma cells

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Abstract Sirtuin-3 (SIRT3) is an important mitochondria NAD+-dependent deacetylase that is known to target mitochondrial proteins for deacetylation and regulates a variety of cellular functions. We have previously shown that SIRT3 was overexpressed in human melanoma cells and tissues and its genetic knockdown resulted in a significant antiproliferative response in human melanoma cells (In: AACR Annual Meeting: Proceedings; 2014 April 5-April 9, San Diego; CA, Abstract # 3516). Our data suggested that small molecule inhibitors of SIRT3 may be developed for the management of melanoma. In this study, we determined the anti-proliferative efficacy of a newly identified small molecule SIRT3 inhibitor, 4′-bromo-resveratrol, in human melanoma cell lines (G361, SK-MEL-28 and SK-MEL-2). Treatment of melanoma cells with 4-bromoresveratrol (0, 12.5, 25, 50, 100, and 200 × 10-3 mM; for 24, 48 and 72 hrs) resulted in a significant decrease in cell proliferation in a dose- and time- dependent manner. In addition, 4′-bromo-resveratrol treatment also resulted in a marked decrease in the growth, viability, clonogenic survival and migration of melanoma cells. Further, the anti-proliferative effects of 4′-bromo-resveratrol were accompanied by a marked downregulation of proliferating cell nuclear antigen (PCNA) protein as well as SIRT3 mRNA and protein. Furthermore, 4′-bromo-resveratrol treatment to melanoma cells resulted in 1) significant induction of apoptosis in melanoma cells, as evident from increase in PARP cleavage, decrease in pro-caspase-3, pro-caspase-8; and 2) G0/G1 phase cell cycle arrest. We also observed a marked increase in WAF-1/p21 protein levels and decreases in cyclin D1 and cdk2 protein levels as a result of 4′-bromo-resveratrol treatment in melanoma cells. Finally, we also found that 4′-bromo-resveratrol caused a metabolic reprograming in human melanoma cells as shown by decreases in the levels of lactate production, glucose uptake, NAD+/NADH ratio, which were accompanied by downregulation in protein levels of lactate dehydrogenase A (LDHA) and glucose transporter 1 (Glut1) in melanoma cells. Collectively, our data suggest that the small molecule SIRT3 inhibitors, including 4′-bromo-resveratrol, may be developed for melanoma management. However, detailed mechanistic studies as well as in vivo validation studies in appropriate animal model(s) are needed to ascertain the clinical potential of 4′-bromo-resveratrol and/or other SIRT3 inhibitors. Citation Format: Jasmine George, Minakshi Nihal, Chandra K. Singh, Nihal Ahmad. Small molecule SIRT3 inhibitor 4′-bromo-resveratrol inhibits proliferation, promotes apoptosis and causes metabolic reprograming of human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1127. doi:10.1158/1538-7445.AM2015-1127