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Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.
University of Manitoba, Canada.
Center for Comparative Respiratory Biology and Medicine, USA.
University of Manitoba, Canada.
University of Manitoba, Canada.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed) In press
Abstract [en]

The mevalonate (MVA) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MVA cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma (U87, U251), neuroblastoma (SH-SY5Y), lung adenocarcinoma (A549, H460, H1650, H1975), and breast cancer (MCF7, MDA-MB231). Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway which included a significant decrease in mitochondrial membrane potential. In all cancer cells tested, simvastatin-induced cell death did not require cholesterol, but was dependent on GGPP and FPP. We confirmed that simvastatin caused the translocation of RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251, A549, and MDA-MB-231 cells. Inhibition of geranylgeranyl transferase I by GGTi-298, but not farnesyl transferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231 cells. These results indicate that MVA cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP in a variety of different cancer cell lines.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017.
Keyword [en]
Simvastatin, non-small cell lung cancer, breast cancer, glioblastoma, neuroblastoma, Rho GTPase, cancer cell biology
National Category
Medical and Health Sciences Basic Medicine Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-134565OAI: oai:DiVA.org:liu-134565DiVA: diva2:1074856
Projects
No
Available from: 2017-02-16 Created: 2017-02-16 Last updated: 2017-02-28Bibliographically approved

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Citation style
  • apa
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  • ieee
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  • vancouver
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More styles
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  • de-DE
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