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

被引：103

作者：

Alizadeh, Javad ^{[1
,2
]}

Zeki, Amir A. ^{[3
]}

Mirzaei, Nima ^{[1
]}

Tewary, Sandipan ^{[1
]}

Moghadam, Adel Rezaei ^{[1
,2
]}

Glogowska, Aleksandra ^{[1
]}

Nagakannan, Pandian ^{[4
]}

Eftekharpour, Eftekhar ^{[4
]}

Wiechec, Emilia ^{[5
]}

Gordon, Joseph W. ^{[1
,6
,7
]}

Xu, Fred. Y. ^{[8
,9
]}

Field, Jared T. ^{[10
]}

Yoneda, Ken Y. ^{[3
]}

Kenyon, Nicholas J. ^{[3
]}

Hashemi, Mohammad ^{[11
]}

Hatch, Grant M. ^{[8
,9
]}

Hombach-Klonisch, Sabine ^{[1
]}

Klonisch, Thomas ^{[1
]}

Ghavami, Saeid ^{[1
,2
,12
]}

机构：

[1] Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Human Anat & Cell Sci, Winnipeg, MB, Canada

[2] Univ Manitoba, Childrens Hosp Res Inst Manitoba, Biol Breathing Theme, Winnipeg, MB, Canada

[3] Ctr Comparat Resp Biol & Med, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Davis, CA USA

[4] Univ Manitoba, Rady Fac Hlth Sci, Max Rady Coll Med, Dept Physiol & Pathophysiol,Regenerat Med,Program, Winnipeg, MB, Canada

[5] Linkoping Univ, Div Otorhinolaryngol, Dept Clin & Expt Moledicine, Linkoping, Sweden

[6] Univ Manitoba, Rady Fac Hlth Sci, Coll Nursing, Winnipeg, MB, Canada

[7] Univ Manitoba, Childrens Hosp Res Inst Manitoba, Coll Nursing, Winnipeg, MB, Canada

[8] Univ Manitoba, DREAM, Childrens Hosp Res Inst Manitoba, Ctr Res & Treatment Atherosclerosis, Winnipeg, MB, Canada

[9] Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada

[10] Univ Manitoba, Fac Sci, Dept Biol Sci, Winnipeg, MB, Canada

[11] Zehedan Univ Med Sci, Dept Clin Biochem, Zahedan, Iran

[12] Shiraz Univ Med Sci, Ctr Hlth Policy Res, Shiraz, Iran

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

基金：

加拿大自然科学与工程研究理事会;

关键词：

LUNG-CANCER CELLS; HMG-COA REDUCTASE; DENSITY-LIPOPROTEIN RECEPTOR; LOVASTATIN-INDUCED APOPTOSIS; STATIN-INDUCED INHIBITION; RHO-GTPASES; FEEDBACK-REGULATION; PROTEIN GERANYLGERANYLATION; MEDIATED APOPTOSIS; NITRIC-OXIDE;

D O I：

10.1038/srep44841

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-MB231( 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.

引用

页数：14

共 96 条

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