Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.
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.
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.|Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.
Javad
J
Alizadeh
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Center for Comparative Respiratory Biology and Medicine, Davis, CA, USA.
Amir A
AA
Zeki
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Nima
N
Mirzaei
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Sandipan
S
Tewary
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.|Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.
Adel
A
Rezaei Moghadam
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Aleksandra
A
Glogowska
Department of Physiology and Pathophysiology, Regenerative Medicine, Program and Spinal Cord research Center, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Pandian
P
Nagakannan
Department of Physiology and Pathophysiology, Regenerative Medicine, Program and Spinal Cord research Center, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Eftekhar
E
Eftekharpour
Department of Clinical and Experimental Moledicine, Division of Otorhinolaryngology, Linköping University, 581-85, Linköping, Sweden.
Emilia
E
Wiechec
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.|College of Nursing and Children's Hospital Research Institute of Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Joseph W
JW
Gordon
DREAM, Children's Hospital Research Institute of Manitoba, Center for Research and Treatment of Atherosclerosis and Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Fred Y
FY
Xu
Department of Biological Sciences, Faculty of Science, University of Manitoba, Winnipeg, Canada.
Jared T
JT
Field
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Center for Comparative Respiratory Biology and Medicine, Davis, CA, USA.
Ken Y
KY
Yoneda
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Center for Comparative Respiratory Biology and Medicine, Davis, CA, USA.
Nicholas J
NJ
Kenyon
Department of Clinical Biochemistry, Zehedan University of Medical Sciences, Zahedan, Iran.
Mohammad
M
Hashemi
DREAM, Children's Hospital Research Institute of Manitoba, Center for Research and Treatment of Atherosclerosis and Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Grant M
GM
Hatch
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Sabine
S
Hombach-Klonisch
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Thomas
T
Klonisch
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.|Biology of Breathing Theme, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada.|Health Policy Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran.
Saeid
S
Ghavami
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008798:Mevalonic Acid / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013729:Terpenes; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D002784:Cholesterol; D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid