4′‐Bromo‐resveratrol, a dual Sirtuin‐1 and Sirtuin‐3 inhibitor, inhibits melanoma cell growth through mitochondrial metabolic reprogramming
Year: 2019
Type: article
Abstract: Sirtuin‐1 and ‐3 (SIRT1 and SIRT3) are important nicotinamide adenine dinucleotide (NAD+)‐dependent deacetylases known to regulate a variety of cellular functions. Studies have shown that SIRT1 and SIRT3 were overexpressed in human melanoma cells and tissues and their inhibition resulted in a significant antiproliferative response in human melanoma cells and antitumor response in a mouse xenograft model of melanoma. In this study, we determined the antiproliferative efficacy of a newly identified dual small molecule inhibitor of SIRT1 and SIRT3, 4′‐bromo‐resveratrol (4′‐BR), in human melanoma cell lines (G361, SK‐MEL‐28, and SK‐MEL‐2). Our data demonstrate that 4′‐BR treatment of melanoma cells resulted in (a) decrease in proliferation and clonogenic survival; (b) induction of apoptosis accompanied by a decrease in procaspase‐3, procaspase‐8, and increase in the cleavage of caspase‐3 and poly (ADP‐ribose) polymerase (PARP); (c) marked downregulation of proliferating cell nuclear antigen (PCNA); and (d) inhibition of melanoma cell migration. Further, 4′‐BR caused a G0/G1 phase arrest of melanoma cells that was accompanied by an increase in WAF‐1/P21 and decrease in Cyclin D1/Cyclin‐dependent kinase 6 protein levels. Furthermore, we found that 4′‐BR causes a decrease in lactate production, glucose uptake, and NAD+/NADH ratio. These responses were accompanied by downregulation in lactate dehydrogenase A and glucose transporter 1 in melanoma cells. Collectively, our data suggest that dual inhibition of SIRT1 and SIRT3 using 4′‐BR imparted antiproliferative effects in melanoma cells through a metabolic reprogramming and affecting the cell cycle and apoptosis signaling. Therefore, concomitant pharmacological inhibition of SIRT1 and SIRT3 needs further investigation for melanoma management.
Source: Molecular Carcinogenesis
DOI: 10.1002/mc.23080
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2962589166