Hydrophobic statins induce autophagy and cell death in human rhabdomyosarcoma cells by depleting geranylgeranyl diphosphate
Hydrophobic statins induce autophagy and cell death in human rhabdomyosarcoma cells by depleting geranylgeranyl diphosphate
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DOI：
10.1016/j.ejphar.2011.10.044
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发表时间：
2012-01-15
影响因子：
5
通讯作者：
Motojima, Kiyoto
中科院分区：
文献类型：
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作者：
Araki, Makoto;Maeda, Masatomo;Motojima, Kiyoto
他汀类药物是治疗高胆固醇血症最常见的药物类型;然而，它们与肌毒性（如肌病和横纹肌溶解）的低发生率相关。不良反应的机制仍有待充分阐明，以便更安全地长期使用和药物开发。我们早期的工作结果表明，疏水性他汀类药物诱导培养的人横纹肌肉瘤A204细胞自噬。在本研究中，我们首先通过评估其他标准来证实他汀类药物诱导的自噬，这些标准包括诱导自噬相关基因的表达，增强自噬标志蛋白p62的蛋白降解以及诱导自噬体形成的电镜观察。我们接下来证明了细胞中HMG-CoA还原酶的抑制程度与他汀类药物诱导自噬的能力平行。因此，他汀类药物的主要活性导致A204细胞中的自噬。考虑到诱导的机制，我们发现他汀类药物通过消耗细胞水平的香叶基香叶基二磷酸（GGPP）诱导自噬，主要是通过一种未知的途径，不涉及两种主要的小G蛋白，Rheb和Ras。最后，我们证明了他汀类药物诱导自噬的能力与其对A204细胞的毒性平行，并且两者都可以被GGPP抑制。(C)2011 Elsevier B. V.保留所有权利。
Statins are the most common type of medicine used to treat hypercholesterolemia; however, they are associated with a low incidence of myotoxicity such as myopathy and rhabdomyolysis. The mechanisms for the adverse effects remain to be fully elucidated for safer chronic use and drug development. The results of our earlier work suggested that hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma A204 cells. In this study, we first confirmed the statin-induced autophagy by assessing other criteria, including induced expression of the autophagy-related genes, enhanced protein degradation of autophagy marker protein p62 and electron microscopic observation of induced formation of autophagosome. We next demonstrated that the extent of inhibition of HMG-CoA reductase in the cell is parallel with the ability of a statin to induce autophagy. Thus, the primary activity of statins causes autophagy in A204 cells. Considering the mechanism for the induction, we showed that statins induce autophagy by depleting cellular levels of geranylgeranyl diphosphate (GGPP) mostly through an unknown pathway that does not involve two major small G proteins, Rheb and Ras. Finally, we demonstrated that the ability of statins to induce autophagy parallels their toxicity to A204 cells and that both can be suppressed by GGPP. (C) 2011 Elsevier B.V. All rights reserved.