Apoptosis of metastatic prostate cancer cells by a combination of cyclin-dependent kinase and AKT inhibitors.
Effective treatments for advanced prostate cancer are much needed. Toward this goal, we show apoptosis and impaired long-term survival of androgen-independent prostate cancer cells (PC3 and PC3 derivatives) co-treated with the cyclin-dependent kinase (CDK) inhibitor roscovitine and an AKT inhibitor (LY294002 or API-2). Apoptosis of PC3 cells by the drug combination required caspase-9 but not caspase-8 activity and thus is mitochondria-dependent. Roscovitine reduced amounts of the caspase inhibitor XIAP, and API-2 increased amounts of the BH3-only protein Bim. PC3 cells apoptosed when co-treated with API-2 and either cdk9 siRNA, dominant-negative cdk9, or the cdk9 inhibitor DRB; they did not apoptose when co-treated with API-2 and XIAP siRNA. Bax accumulated in mitochondria in response to API-2, whereas release of cytochrome c from mitochondria required both API-2 and roscovitine. We suggest that roscovitine elicits events that activate Bax once it translocates to mitochondria and that inactivation of cdk9 signals these events and the down-regulation of XIAP. Collectively, our data show apoptosis of prostate cancer cells by a drug combination and identify Bax activation as a basis of cooperation.
Mohapatra
Subhra
S
Molecular Oncology Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Chu
Baoky
B
Zhao
Xiuhua
X
Djeu
Julie
J
Cheng
Jin Q
JQ
Pledger
W Jackson
WJ
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000096:biosynthesis; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000077546:Roscovitine; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D000096926:Benzenesulfonamides
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D053453:Caspase 9; D002747:Chlorpropamide; D002867:Chromones; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D004247:DNA; D004004:Dichlororibofuranosylbenzimidazole; D008565:Membrane Proteins; D009025:Morpholines; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D034741:RNA, Small Interfering; D000077546:Roscovitine; D051636:X-Linked Inhibitor of Apoptosis Protein; C111224:API 2; D000096926:Benzenesulfonamides; C000606775:BCL2L11 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one