Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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Persistent P21Cip1 Induction Mediates G1 Cell Cycle Arrest by Methylseleninic Acid in DU145 Prostate Cancer Cells

Author(s): Z. Wang, H.-J. Lee, Y. Chai, H. Hu, L. Wang, Y. Zhang, C. Jiang, J. Lu.

Abstract:

The induction of G1 cell cycle arrest and apoptosis by second-generation selenium compounds (e.g., methylselenol precursors such as methylseleninic acid, MSeA) may contribute to their anti-cancer activities. We have documented previously induction of G1 arrest and apoptosis by MSeA in association with upregulation of cyclin-dependent kinase inhibitor (CDKI) proteins P21Cip1 and/or P27Kip1 in DU145 prostate cancer cells. However, whether these CDKIs play a critical mediator role in G1 arrest and apoptosis by MSeA has not been addressed. In the present work, we show exposure of p53-mutant DU145 cells to sub-apoptotic concentrations of MSeA induced p21cip1 mRNA (3 h) and protein (6 h) much faster than p27kip1 mRNA (12 h) and protein (12 h). Knocking down of P21Cip1 by siRNA completely abolished G1 arrest induction by MSeA in DU145 cells, yet si-p27 RNA had no attenuation effect on the G1 arrest. Depletion of P21Cip1 alone or both P21Cip1 and P27Kip1 increased MSeA-induced caspase-mediated apoptosis. Immunoprecipitation detected increased binding of P21Cip1 to CDK2 and CDK6 in MSeA-exposed DU145 cells. In DU145 xenografts from mice acutely treated with MSeA p.o., the induction of P21Cip1 was observed at 72 h of daily exposure. In p53-wild type LNCaP PCa cells and p53-null PC-3 PCa cells, MSeA modestly and transiently upregulated P21Cip1 protein level, subsiding to basal level by 24 h, without affecting P27Kip1 abundance in the same duration. Si-p21 RNA knockdown in these cells have only a partial effect to reverse G1 arrest induction by MSeA. Together, our data support persistent, p53- independent, P21Cip1 induction as a critical mediator of MSeA-induced G1 arrest in DU145 PCa cells, however, P21Cip1 induction and G1 arrest were not necessary for, and may antagonize, caspase-mediated apoptosis.

Keywords: Selenium, G1 arrest, P21Cip1, siRNA knockdown, prostate cancer

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Article Details

VOLUME: 10
ISSUE: 3
Year: 2010
Page: [307 - 318]
Pages: 12
DOI: 10.2174/156800910791190238
Price: $58