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

Anna Goc, Samith T. Kochuparambil, Belal Al-Husein, Ahmad Al-Azayzih, Shuaib Mohammad, Payaningal R. Somanath

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

Abstract

Background: Recent 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.Methods: Effect 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.Results: Data 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.Conclusions: Our 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.

Original languageEnglish
Article number409
JournalBMC Cancer
Volume12
DOIs
Publication statusPublished - Sep 14 2012
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Docetaxel
  • Fas-L
  • Prostate cancer
  • Simvastatin

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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