Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells.
Toward the goal of developing effective treatments for prostate cancers, we examined the effects of cyclin-dependent kinase inhibitors on the survival of prostate cancer cells. We show that roscovitine, R-roscovitine, and CGP74514A (collectively referred to as CKIs) induce the apoptosis of LNCaP and LNCaP-Rf cells, both of which express wild-type p53. Apoptosis required caspase-9 and caspase-3 activity, and cytochrome c accumulated in the cytosol of CKI-treated cells. Amounts of p53 increased substantially in CKI-treated cells, whereas amounts of the endogenous caspase inhibitor XIAP decreased. CKIs did not appreciably induce the apoptosis of LNCaP cells treated with pifithrin-alpha, which prevents p53 accumulation, or of prostate cancer cells that lack p53 function (PC3 and DU145). Ectopic expression of p53 in PC3 cells for 44 hours did not reduce XIAP abundance or induce apoptosis. However, p53-expressing PC3 cells readily apoptosed when exposed to CKIs or when depleted of XIAP by RNA interference. These findings show that CKIs induce the mitochondria-mediated apoptosis of prostate cancer cells by a dual mechanism: p53 accumulation and XIAP depletion. They suggest that these events in combination may prove useful in the treatment of advanced prostate cancers.
Mohapatra
Subhra
S
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute and University of South Florida Medical Center, Tampa, Florida 33612, USA. mohapts@moffitt.usf.edu
Chu
Baoky
B
Zhao
Xiuhua
X
Pledger
W J
WJ
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; C469937:N(2)-(2-aminocyclohexyl)-N(6)-(3-chlorophenyl)-9-ethyl-9H-purine-2,6-diamine; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011687:Purines; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077546:Roscovitine; D015075:2-Aminopurine; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases