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辛伐他汀对神经胶质瘤细胞增殖、迁移和凋亡的影响。

Effect of simvastatin on glioma cell proliferation, migration, and apoptosis.

机构信息

Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan 48202, USA.

出版信息

Neurosurgery. 2009 Dec;65(6):1087-96; discussion 1096-7. doi: 10.1227/01.NEU.0000360130.52812.1D.

DOI:10.1227/01.NEU.0000360130.52812.1D
PMID:19934968
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3711082/
Abstract

OBJECTIVE

In this study, we investigated the effects of simvastatin on proliferation, migration, and apoptosis in human U251 and U87 glioma cells and the underlying molecular mechanism.

METHODS

We used colony formation assay to test the cell proliferation, in vitro scratch assay to examine the cell migration, and caspase-3 activity assay, annexin V staining, and cytochrome C release to evaluate the cell apoptosis. Lipid raft fractions were isolated from glioma cells. Total cholesterol content assay was used to test the change of cholesterol level in lipid raft fractions. Immunocytochemistry staining was performed to detect the changes of lipid rafts in cell membranes. Western blotting analysis was performed to examine the signal transduction both in cells and in lipid raft fractions.

RESULTS

Simvastatin inhibited proliferation and migration of U251 and U87 cells dose dependently. Simvastatin induced an increase of caspase-3 activity and annexin V staining, and down-regulated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Simvastatin also decreased cholesterol content in lipid raft fractions, suppressed caveolin-1 expression in the lipid rafts, and induced Fas translocation into lipid rafts, suggesting that simvastatin may inhibit the prosurvival PI3K/Akt pathway and trigger caspase-3-dependent apoptotic cell death through the modulation of lipid rafts.

CONCLUSION

These results suggest that modulation of lipid rafts, Fas translocation, and PI3K/Akt/caspase-3 pathway are involved in the antitumor effect of simvastatin and may have a potential role in cancer prevention and treatment.

摘要

目的

本研究旨在探讨辛伐他汀对人 U251 和 U87 神经胶质瘤细胞增殖、迁移和凋亡的影响及其潜在的分子机制。

方法

采用集落形成实验检测细胞增殖，体外划痕实验检测细胞迁移，caspase-3 活性检测、Annexin V 染色和细胞色素 C 释放实验评估细胞凋亡。从神经胶质瘤细胞中分离脂质筏，用总胆固醇含量测定检测脂质筏中胆固醇水平的变化。免疫细胞化学染色检测细胞膜中脂质筏的变化。Western blot 分析用于检测细胞和脂质筏中的信号转导。

结果

辛伐他汀呈剂量依赖性地抑制 U251 和 U87 细胞的增殖和迁移。辛伐他汀诱导 caspase-3 活性和 Annexin V 染色增加，下调磷酸肌醇 3-激酶（PI3K）/Akt 通路。辛伐他汀还降低了脂质筏中的胆固醇含量，抑制了脂质筏中的窖蛋白-1 表达，并诱导 Fas 向脂质筏内转位，提示辛伐他汀可能通过调节脂质筏抑制促生存的 PI3K/Akt 通路，并通过 Fas 诱导 caspase-3 依赖性细胞凋亡。

结论

这些结果表明，脂质筏的调节、Fas 的转位以及 PI3K/Akt/caspase-3 通路参与了辛伐他汀的抗肿瘤作用，可能在癌症的预防和治疗中有一定作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/a48a1e12e86e/nihms486595f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/39bbf01faf0c/nihms486595f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/dcf151f05bce/nihms486595f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/ee69541e5dc6/nihms486595f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/de24f3c11f19/nihms486595f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/f5a004424730/nihms486595f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/4c24bfe3a011/nihms486595f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/a48a1e12e86e/nihms486595f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/39bbf01faf0c/nihms486595f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/dcf151f05bce/nihms486595f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/ee69541e5dc6/nihms486595f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/de24f3c11f19/nihms486595f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/f5a004424730/nihms486595f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/4c24bfe3a011/nihms486595f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f139/3711082/a48a1e12e86e/nihms486595f7.jpg

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