BACKGROUND: Resveratrol, 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 FINDINGS: Resveratrol 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/SIGNIFICANCE: These data suggest that FOXO transcription factors 
mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due 
to activation of extrinsic apoptosis pathway.