Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

BMC Cancer

Research Article

Shuaib Mohammad¹  Anna Goc²  Belal Al-Husein²  Ahmad Al-Azayzih²  Samith T Kochuparambil³  Payaningal R Somanath⁴ 

[1] Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA;Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA;Charlie Norwood VA Medical Center, Augusta, GA, USA;Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA;Charlie Norwood VA Medical Center, Augusta, GA, USA;Department of Medicine, Georgia Health Sciences University, Augusta, GA, USA;Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA;Charlie Norwood VA Medical Center, Augusta, GA, USA;Department of Medicine, Georgia Health Sciences University, Augusta, GA, USA;Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, HM1200 – Georgia Health Sciences University, 30912, Augusta, GA, USA;

关键词: Prostate cancer;    Simvastatin;    Docetaxel;    Apoptosis;    Bcl-2;    Fas-L;   

DOI  :  10.1186/1471-2407-12-409

 received in 2012-04-14, accepted in 2012-09-11,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundRecent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood.MethodsEffect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin.ResultsData indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5.ConclusionsOur study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent.

【 授权许可】

Unknown   
© Goc et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.