Suppression of human prostate cancer cell growth by β-lapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor P21 WAF1/CIP1

Abstract

The product of a tree (Tabebuia avellanedae) from South America, β-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 β-lapachone exerts its anti-proliferative action in cultured human prostate cancer cells. We observed that the proliferation-inhibitory effect of β-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 β-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, β-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 p21WAF1/CIP1 expression in a p53-indcpendent manner, and the p21 proteins that were induced by β-lapachone were associated with Cdk2. β-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 β-lapachone. This may explain some of its anti-cancer effects. © KSBMB & Springer-Verlag 2003.