Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated apoptosis through multiple mechanisms.
BACKGROUND
A critical factor in prostate cancer development and progression is the altered expression of apoptotic regulatory proteins which renders cells resistant to both hormone- and chemo-therapies. Resveratrol, a dietary component with chemopreventive properties has been reported to resensitize a variety of cancer cell types to apoptosis. In the current study, the ability of resveratrol pre-treatment to sensitize hormone refractory prostate cancer cell lines (PC-3 and DU145) to apoptosis and the mechanisms involved were investigated.


METHODS
Apoptosis was assessed using several established parameters and protein expression was analyzed by Western blot and flow cytometry. IAP knockdown was achieved using RNAi while inhibition of Akt phosphorylation was achieved by pre-incubation with the PI3-kinase inhibitor LY294002.


RESULTS
Pre-treatment with resveratrol sensitized PC-3 and DU145 cells to agents that specifically target death receptors (TRAIL, Fas, TNFalpha) but not agents that initiate apoptosis through other mechanisms (Etoposide, Paclitaxel, Tunicamycin, Thapsigargin). Resveratrol pre-treatment altered the expression of IAPs and Bax, and decreased Akt phosphorylation in PC-3 cells, leading to increased caspase activation and apoptosis. While knockdown of IAPs using siRNA did not mimic the effects of resveratrol, inhibition of Akt phosphorylation using LY294002 sensitized PC-3 cells to TRAIL induced apoptosis but not to etoposide or tunicamycin.


CONCLUSIONS
Altering apoptotic susceptibility in advanced androgen independent disease requires manipulation of a broad signaling pathway. Use of resveratrol or inhibition of Akt phosphorylation may represent an important therapeutic approach in combination with conventional therapies for the treatment of prostate cancer.
Gill
Catherine
C
UCD School of Medicine and Medical Sciences, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland. catherine.gill@ucd.ie
Walsh
Sinead E
SE
Morrissey
Colm
C
Fitzpatrick
John M
JM
Watson
R William G
RW
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects / Q000235:genetics; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053218:Receptors, Death Domain / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases