Suppression of human prostate cancer cell growth by beta-lapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21(WAF1/CIP1).
The product of a tree (Tabebuia avellanedae) from South America, beta-lapachone, is known to exhibit various pharmacological properties, the mechanisms of which are poorly understood. The aim of the present study was to further elucidate the possible mechanisms by which beta-lapachone exerts its anti-proliferative action in cultured human prostate cancer cells. We observed that the proliferation-inhibitory effect of beta-lapachone was due to the induction of apoptosis, which was confirmed by observing the morphological changes and cleavage of the poly(ADP-ribose) polymerase protein. A DNA flow cytometric analysis also revealed that beta-lapachone arrested the cell cycle progression at the G1 phase. The effects were associated with the down-regulation of the phosphorylation of the retinoblastoma protein (pRB) as well as the enhanced binding of pRB and the transcription factor E2F-1. Also, beta-lapachone suppressed the cyclin-dependent kinases (Cdks) and cyclin E-associated kinase activity without changing their expressions. Furthermore, this compound induced the levels of the Cdk inhibitor p21(WAF1/CIP1) expression in a p53-independent manner, and the p21 proteins that were induced by beta-lapachone were associated with Cdk2. beta-lapachone also activated the reporter construct of a p21 promoter. Overall, our results demonstrate a combined mechanism that involves the inhibition of pRB phosphorylation and induction of p21 as targets for beta-lapachone. This may explain some of its anticancer effects.
Choi
Yung Hyun
YH
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University and Research Center for Oriental Medicine, Pusan 614-052, Korea. choiyh@dongeui.ac.kr
Kang
Ho Sung
HS
Yoo
Mi-Ae
MA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis* / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D008297:Male; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009285:Naphthoquinones; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C014638:beta-lapachone; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases