Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

• DOI: 10.1038/srep44841
• Publication Date: 2017-03-27T08:59:10Z
• Authors: Javad Alizadeh; Amir A. Zeki; Nima Mirzaei; Sandipan Tewary; Adel Rezaei Moghadam; Aleksandra Glogowska; Pandian Nagakannan; Eftekhar Eftekhar...; Emilia Wiechec; Joseph W. Gordon; Fred. Y. Xu; Jared T. Field; Ken Y. Yoneda; Nicholas J. Kenyon; Mohammad Hashemi; Grant M. Hatch; Sabine Hombach-Kl...; Thomas Klonisch; Saeid Ghavami
• Keywords: Lovastatin; Geranylgeranylation

Abstract The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of intermediate metabolites geranylgeranylpyrophosphate (GGPP) farnesylpyrophosphate (FPP) used in prenylation proteins. Here we show that MEV inhibitor simvastatin induced significant cell death a wide range human tumor lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, breast cancer. Simvastatin apoptotic via intrinsic pathway. In all cancer types tested, simvastatin-induced was not rescued by cholesterol, but dependent on GGPP- FPP-depletion. We confirmed caused translocation small Rho GTPases RhoA, Cdc42, Rac1/2/3 from membranes to cytosol U251 (glioblastoma), A549 (lung adenocarcinoma) MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased cells which were reversed with MEV, FPP, GGPP. contrast, did change MDA-MB-231. Inhibition geranylgeranyltransferase I GGTi-298, farnesyltransferase FTi-277, U251, A549, These results indicate inhibition apoptosis pathway family depletion GGPP, variety different lines.