Resveratrol regulates Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT, mitochondrial p53 and apoptosis in prostate cancer cells.

A37

Resveratrol, an active ingredient derived from grapes and red wine, has anticancer activity. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. Resveratrol inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Resveratrol downregulated the expression of Bcl-2, and Bcl-X_L and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Resveratrol upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation. Treatment of LNCaP cells with resveratrol resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, resveratrol inhibited phosphatidylinositol-3 kinase (PI3K) / AKT pathway, and downregulation of AKT increased resveratrol-induced apoptosis. Overexpression of constitutively active AKT inhibited resveratrol-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced resveratrol-induced p53 translocation to mitochondria and Smac release. Resveratrol also induced the acetylation of histone H3 and H4, suggesting histone modification may regulate gene expression. Our study establishes a role for AKT inmodulating the direct action of p53 on the caspase-dependent mitochondria l death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence resveratrol sensitivity. These properties of resveratrol strongly suggest that it could be used as a cancer chemopreventive agent.