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

Javad Alizadeh, Amir Zeki, Nima Mirzaei, Sandipan Tewary, Adel Rezaei Moghadam, Aleksandra Glogowska, Pandian Nagakannan, Eftekhar Eftekharpour, Emilia Wiechec, Joseph W. Gordon, Fred Y. Xu, Jared T. Field, Ken Y Yoneda, Nicholas Kenyon, Mohammad Hashemi, Grant M. Hatch, Sabine Hombach-Klonisch, Thomas Klonisch, Saeid Ghavami

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Abstract

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

Original languageEnglish (US)
Article number44841
JournalScientific Reports
Volume7
DOIs
StatePublished - Mar 27 2017

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Mevalonic Acid
Simvastatin
Terpenes
Apoptosis
Cell Death
Neoplasms
Glioblastoma
Guanosine Triphosphate
Cholesterol
Protein Prenylation
Breast Neoplasms
Farnesyltranstransferase
Prenylation
rho GTP-Binding Proteins
Monomeric GTP-Binding Proteins
Astrocytoma
Tumor Cell Line
Neuroblastoma
Cytosol
Lung Neoplasms

ASJC Scopus subject areas

  • General

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Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells. / Alizadeh, Javad; Zeki, Amir; Mirzaei, Nima; Tewary, Sandipan; Rezaei Moghadam, Adel; Glogowska, Aleksandra; Nagakannan, Pandian; Eftekharpour, Eftekhar; Wiechec, Emilia; Gordon, Joseph W.; Xu, Fred Y.; Field, Jared T.; Yoneda, Ken Y; Kenyon, Nicholas; Hashemi, Mohammad; Hatch, Grant M.; Hombach-Klonisch, Sabine; Klonisch, Thomas; Ghavami, Saeid.

In: Scientific Reports, Vol. 7, 44841, 27.03.2017.

Research output: Contribution to journalArticle

Alizadeh, J, Zeki, A, Mirzaei, N, Tewary, S, Rezaei Moghadam, A, Glogowska, A, Nagakannan, P, Eftekharpour, E, Wiechec, E, Gordon, JW, Xu, FY, Field, JT, Yoneda, KY, Kenyon, N, Hashemi, M, Hatch, GM, Hombach-Klonisch, S, Klonisch, T & Ghavami, S 2017, 'Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells', Scientific Reports, vol. 7, 44841. https://doi.org/10.1038/srep44841
Alizadeh, Javad ; Zeki, Amir ; Mirzaei, Nima ; Tewary, Sandipan ; Rezaei Moghadam, Adel ; Glogowska, Aleksandra ; Nagakannan, Pandian ; Eftekharpour, Eftekhar ; Wiechec, Emilia ; Gordon, Joseph W. ; Xu, Fred Y. ; Field, Jared T. ; Yoneda, Ken Y ; Kenyon, Nicholas ; Hashemi, Mohammad ; Hatch, Grant M. ; Hombach-Klonisch, Sabine ; Klonisch, Thomas ; Ghavami, Saeid. / Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells. In: Scientific Reports. 2017 ; Vol. 7.
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AU - Tewary, Sandipan

AU - Rezaei Moghadam, Adel

AU - Glogowska, Aleksandra

AU - Nagakannan, Pandian

AU - Eftekharpour, Eftekhar

AU - Wiechec, Emilia

AU - Gordon, Joseph W.

AU - Xu, Fred Y.

AU - Field, Jared T.

AU - Yoneda, Ken Y

AU - Kenyon, Nicholas

AU - Hashemi, Mohammad

AU - Hatch, Grant M.

AU - Hombach-Klonisch, Sabine

AU - Klonisch, Thomas

AU - Ghavami, Saeid

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