Abstract
BackgroundResveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. 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. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol.Methodology/Principal FindingsResveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin) and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM) induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and apoptosis, and inhibition of cyclin D1 by resveratrol.Conclusion/SignificanceThese data suggest that FOXO transcription factors mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due to activation of extrinsic apoptosis pathway.
Highlights
Prostate cancer, one of the more common neoplasms in the western world, arises through the progressive development of one or more pre neoplastic lesions into adenocarcinoma, and subsequently to metastatic disease [1]
Since LNCaP cells express constitutively active AKT, we sought to examine the role of PI3K/AKT pathway on resveratrol-induced apoptosis
The combination of LY294002 or AKT inhibitor IV with resveratrol had no further effect on the expression of p27/KIP1 and cyclin D1. These data suggest that inhibition of PI3K/AKT pathway can regulate the expression of Bim, p27/Kip1, cyclin D1, TRAIL, DR4 and DR5, which are transcriptional targets of FOXO
Summary
One of the more common neoplasms in the western world, arises through the progressive development of one or more pre neoplastic lesions into adenocarcinoma, and subsequently to metastatic disease [1]. Recent advances have identified key genetic alterations that can initiate prostate carcinogenesis, and enhance the probability of cancer progression. Prostate cancer cells are only modestly responsive or even unresponsive to the cytotoxic effects of chemotherapeutic agents or radiotherapy. Resveratrol has been shown to exhibit several potential chemoprotective activities in cell and animal models [2,3,4,5,6,7,8,9], including inhibition of PI3K/AKT pathway [2,6,8,10]. Deletion or mutation of PTEN has been the main cause for constitutively active AKT leading to prostate carcinogenesis in humans [11,12]. Resveratrol may be potential candidate to target cells with PTEN deletion or inactivation and enhanced AKT activity in precancerous prostate tissue. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol
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