Resveratrol antagonizes EGFR-dependent Erk1/2 activation in human androgen-independent prostate cancer cells with associated isozyme-selective PKC alpha inhibition.
The development of androgen-independent prostate cancer (AI PrCa) involves constitutive Erk1/2 activation sustained by the epidermal growth factor/transforming growth factor-alpha/EGF receptor (EGF/TGFalpha/EGFR) axis and other trophic signaling mechanisms in neoplastic human prostate epithelial cells in vivo. In this report, we show that growth-inhibitory concentrations of the dietary phytochemical resveratrol suppress EGFR-dependent Erk1/2 activation pathways stimulated by EGF and phorbol ester (12- O -tetradecanoyl phorbol 13-acetate, TPA) in human AI PrCa PC-3 cells in vitro. Because protein kinase C (PKC) is the major cellular receptor for phorbol esters and taking into consideration that resveratrol is PKC-inhibitory, we investigated resveratrol effects on cellular PKC isozymes associated with the suppression of TPA-induced Erk1/2 activation. The PKC isozyme composition of PC-3 cells was defined by Western analysis of the cell lysate with a comprehensive set of isozyme-selective PKC Ab's. PC-3 cells expressed PKCalpha, epsilon, zeta, iota, and PKD (PKCmicro), as did another human AI PrCa cell line of distinct genetic origin, DU145. The effects of resveratrol on TPA-induced PKC isozyme activation were defined by monitoring PKC isozyme translocation and autophosphorylation. Under conditions where resveratrol suppressed TPA-induced Erk1/2 activation, the phytochemical produced isozyme-selective interference with TPA-induced translocation of cytosolic PKCalpha to the membrane/cytoskeleton and selectively diminished the amount of autophosphorylated PKCalpha in the membrane/cytoskeleton of the TPA-treated cells. These results demonstrate that resveratrol abrogation of a PKC-mediated Erk1/2 activation response in PC-3 cells correlates with isozyme-selective PKCalpha inhibition. The results provide evidence that resveratrol may have value as an adjuvant cancer therapeutic in advanced prostate cancer.
Stewart
Jubilee R
JR
Department of Cancer Biology, U.T.M.D. Anderson Cancer Center, Houston, TX 77030, USA.
O'Brian
Catherine A
CA
D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051571:Protein Kinase C-alpha; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
D000728:Androgens; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013267:Stilbenes; D066246:ErbB Receptors; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol