Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.
Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.
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DOI：
10.1038/srep44841
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发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Ghavami S
中科院分区：
文献类型：
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作者：
Alizadeh J;Zeki AA;Mirzaei N;Tewary S;Rezaei Moghadam A;Glogowska A;Nagakannan P;Eftekharpour E;Wiechec E;Gordon JW;Xu FY;Field JT;Yoneda KY;Kenyon NJ;Hashemi M;Hatch GM;Hombach-Klonisch S;Klonisch T;Ghavami S
甲羟戊酸(MEV)级联反应负责胆固醇的生物合成和蛋白质预烯基化过程中中间代谢物香叶基香叶基焦磷酸(GGPP)和法尼基焦磷酸(FPP)的形成。在这里，我们展示了MEV级联抑制剂辛伐他汀在包括胶质母细胞瘤、星形细胞瘤、神经母细胞瘤、肺腺癌和乳腺癌在内的广泛的人类肿瘤细胞系中诱导显著的细胞死亡。辛伐他汀通过内源性细胞凋亡途径诱导细胞凋亡。在所有被测试的癌细胞类型中，辛伐他汀诱导的细胞死亡不能被胆固醇挽救，而是依赖于GGPP和FPP的耗尽。我们证实，在U251(胶质母细胞瘤)、A549(肺腺癌)和MDA-MB-231(乳腺癌)中，辛伐他汀导致小Rho GTP酶RhoA、CDC42和rac1/2/3从细胞膜转位到胞浆。辛伐他汀诱导的U251细胞Rho-GTP载量显著增加，而MEV、FPP、GGPP则相反。相反，辛伐他汀没有改变A549和MDA-MB-231中的Rho-GTP载量。GGTI-298抑制香叶基香叶基转移酶I，而FTI-277不抑制法尼基转移酶，诱导U251、A549和MDA-MB-231细胞显著死亡。这些结果表明，辛伐他汀通过抑制Rho家族的预烯基化和GGPP的耗竭，在多种不同的人类癌细胞系中诱导了内源性的细胞凋亡途径。
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.