Abstract
The polyphenol piceatannol has shown inhibition against tyrosine and serine/threonine kinases. Whether piceatannol also exerts activity on the mammalian target of rapamycin (mTOR), a kinase involved in growth control of eukaryotic cells, is not known. In this study, we tested the effects of piceatannol on proliferation of androgen-dependent (AD) LNCaP and androgen-independent (AI) DU145 and PC-3 prostate cancer (CaP) cells. Suppression of AD and AI CaP cell growth by piceatannol was accompanied by cell cycle blockade in G1/S and S phases for LNCaP and PC-3 and induction of apoptosis in DU145 cells. Induction of apoptosis by piceatannol in DU145 cells was evident by reduced expression of poly(ADP-ribose) polymerase (PARP), cleavage of caspase 3 and apoptosis inducing factor AIF, and an increase in cytochrome c. The apoptotic changes occurred in concordance with DNA damage, supported by increased phosphorylated histone H2AX. Immunoblot analyses showed that exposure of different-stage CaP cells to piceatannol also resulted in cell-type-specific downregulation of mTOR and its upstream and downstream effector proteins, AKT and eIF-4E-BP1. We propose that the observed AKT and mTOR changes are new targets of piceatannol possibly contributing to its inhibitory activities on proliferation of CaP cells.
Highlights
Piceatannol (3,3,4,5 -tetrahydroxy-trans-stilbene) is a polyphenol found in food sources such as grapes, berries, peanuts, and sugar cane [1,2,3,4]
Human LNCaP, DU145, and PC-3 cells were obtained from the American Tissue Culture Collection (Manassas, VA) and cultured in RPMI 1640 supplemented with penicillin, streptomycin, and 10% heat-inactivated Fetal bovine serum (FBS), as described [29]
In previous studies by Kim and coworkers, DU145 cells maintained in DMEM/F12 culture media supplemented with 1% charcoal-treated FBS were followed by h serum deprivation and treatment by piceatannol; exposure to the polyphenol inhibited cell proliferation and induction of apoptosis [25]
Summary
Piceatannol (3,3 ,4,5 -tetrahydroxy-trans-stilbene) is a polyphenol found in food sources such as grapes, berries, peanuts, and sugar cane [1,2,3,4]. Recent studies show that piceatannol inhibits proliferation and induces cell cycle arrest and apoptosis in DU145 CaP cells [24,25,26] and that the anticellular effects of piceatannol are mediated by suppression of the cyclin-dependent protein kinase activities (CDKs) [26]. These results suggest that piceatannol might have chemopreventive potential for. We tested the hypothesis that piceatannol controls proliferation of both androgen-dependent (AD) and rogen-independent (AI) CaP cells by targeting the expression of mTOR. AD and AI CaP cell proliferation and that its growth inhibitory activity was accompanied by reduced expression of mTOR and its key effectors AKT and eIF4EBP-1
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