Statins類藥物誘導人類大腸癌細胞死亡的分子機轉探討

Molecular Mechanisms of Statins-Induced Colon Cancer Cell Death

徐翊庭(Yi-Ting Shu)

指導教授 ： 許銘仁

共同指導教授 ： 許準榕

臺北醫學大學/醫學院/醫學科學研究所/碩士(2011年)

https://doi.org/10.6831/TMU.2011.00127

摘要

Statins是一種3-hydroxy-3-methylglutaryl coenzyme A還原酶的抑制劑，除了具有降低血中膽固醇的特性之外，在治療癌症方面也具有許多不同的抗癌功效。然而statins的抗癌分子機轉仍有許多尚待釐清的地方。在本篇中發現statins會引起HCT116、HT29和colo205癌細胞的細胞週期滯留和細胞凋亡。Survivin是一種會抑制細胞凋亡的蛋白，在細胞的存活和細胞週期進展上扮演很重要的地位。最近的研究指出survivin在許多種類的癌細胞中會大量表現包括大腸癌細胞。藉由在HCT116細胞中轉染survivin siRNA發現可以誘導細胞凋亡和細胞週期滯留。這些結果都指出survivin在HCT116細胞中也一樣占有重要的地位。Lovastatin、pravastatin和simvastatin可以增加p21的基因轉錄活性和減少survivin的基因轉錄活性。此外simvastatin會增加p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK)的磷酸化程度。Simvastatin也會增加p53磷酸化和乙醯化的程度。p53是重要的轉錄因子，有研究證明p53會激活p21和抑制survivin的表現量。在本篇中加入了p38MAPK的抑制劑，結果發現可以反轉simvastatin對p53、p21和survivin蛋白質表現量的作用。Histone acetyltransferase的抑制劑(anacardic acid)會減少simvastatin降低大腸癌細胞存活率的作用。總而言之，statins可能會透過活化p38MAPK-p53的訊息傳遞路徑，進而增加p21的表現量和負向調節survivin，最後使HCT116癌細胞進行細胞凋亡和細胞週期滯留。

關鍵字

細胞凋亡 ； 細胞週期滯留 ； 大腸癌細胞

並列摘要

Statins, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with cholesterol-lowering properties, exhibits anticancer effects in a variety of tumors. However, the molecular mechanisms of statins in anticancer remain to be elucidated. In this study, we demonstrated that statins caused cell cycle arrest and apoptosis in HCT116, HT29 and colo205 colon cancer cells. Survivin, an inhibitor of apoptosis protein (IAP), plays critical roles in cell survival and cell cycle progression. Recent studies reported that survivin is over-expressed in a variety of cancer cells including colon cancer. Transfection of HCT116 cells with the survivin siRNA increased cell apoptosis and induced cell cycle arrest, suggesting the important roles of survivin in HCT116 cancer cells. Lovastatin, pravastatin and simvastatin were shown to increase p21 promoter luciferase activity and to decrease survivin promoter activity. In addition, simvastatin increased p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK) phosphorylation. Simvastatin also increased phosphorylation and acetylation of p53, an important transcription factor which transactivates p21 and suppresses survivin. Inhibitor of p38MAPK signaling reversed the effect of simvastatin on p53, p21, and survivin expression. Simvastatin-decreased cell viability was restored by the presence of anacardic acid, an inhibitor of histone acetyltransferase (HAT). Taken together, statins may activate p38MAPK -p53 signaling cascade, leading to p21 expression and survivin down-regulation, which induced HCT116 colon cancer cells apoptosis and cell cycle arrest.

並列關鍵字

statins ； poptosis ； cell cycle arrest ； survivin ； p21 ； p53

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