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 language | English (US) |
|---|---|
| Article number | 44841 |
| Journal | Scientific Reports |
| Volume | 7 |
| DOIs | |
| State | Published - Mar 27 2017 |
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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 journal › Article
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TY - JOUR
T1 - Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells
AU - Alizadeh, Javad
AU - Zeki, Amir
AU - Mirzaei, Nima
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
PY - 2017/3/27
Y1 - 2017/3/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016143851&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016143851&partnerID=8YFLogxK
U2 - 10.1038/srep44841
DO - 10.1038/srep44841
M3 - Article
C2 - 28344327
AN - SCOPUS:85016143851
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 44841
ER -