simvastatin藥物誘導人類大腸癌細胞死亡的分子機轉探討

Statins藥物是一種3-hydroxy-3-methylglutaryl coenzyme A還原?〞漣磻蹌砥A臨床上用於降低膽固醇，最近研究指出statins類藥物可能具有抗腫瘤活性，但statins類藥物誘導腫瘤細胞死亡的分子機制仍未完全釐清。Survivin為抑制細胞凋亡蛋白 (inhibitors of apoptosis protein, IAP)家族成員之一，被發現會大量表現於人類癌症包括大腸癌細胞中，同時survivin也可能與腫瘤的形成與惡化有關。除了抑制細胞凋亡，survivin在細胞分裂過程也扮演重要角色，因此survivin被認為是具潛力的治療大腸直腸癌標的蛋白。在本論文，我們探討statins類藥物誘導HCT116大腸直腸癌細胞凋亡的作用機轉。Simvastatin 會降低HCT116細胞存活率與誘導細胞凋亡，simvastatin也會誘導p21表現和降低survivin的表現。將細胞轉染survivin siRNA 會顯著降低細胞存活率並誘導細胞凋亡。報告基因實驗結果顯示simvastatin會降低survivin 基因轉錄活性，同時增加 p21 基因轉錄活性，simvastatin降低細胞存活率的作用會被p53抑制劑pifithrin減弱。此外simvastatin會誘導增加p53蛋白的磷酸化和乙醯化，simvastatin更會活化p38 mitogen-activated protein kinase (p38MAPK)，而抑制p38MAPK訊息路徑會抑制simvastatin所增加之p53和p21的基因轉錄活性，也會抑制simvastatin降低survivin基因轉錄活性的作用。綜而言之，由這些結果推測 simvastatin可透過活化p38MAPK，使得p53磷酸化以及活性增加，進而調控p21和survivin的表現，最終造成HCT116大腸直腸癌細胞存活率下降和細胞凋亡。

關鍵字

Statins藥物、Survivin、細胞凋亡

並列摘要

Statins, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors with cholesterol-lowering properties, were recently shown to exhibit anticancer effects in a variety of tumors.Elevated level of survivin, a member of inhibitors of apoptosis protein (IAP), is often found over-expressed in human cancers, including colorectal cancer, and has been implicated in the development and progression of tumorigenesis. Because of survivin plays a central role in cell division and also act as a suppressor of apoptosis, it thus represents a potential molecular target in colorectal cancer management.However, the molecular mechanisms underlying statins-induced cell death in cancer cells remains to be elucidated. In this study, we explored the underlying signaling mechanisms in simvastatin-induced survivin downregulation and cell apoptosis in HCT116 colorectal cancer cells. Simvastatin decreased cell viability and induced cell apoptosis in HCT116 cells. These results are associated with the modulation of p21 and survivin. Survivin knockdown using a survivin small interfering RNA strategy also decreased cell viability and induced cell apoptosis in HCT116 cells. Survivin promoter luciferase activity was decreased while p21 promoter luciferase activity was increased in cells exposed to simvastatin. Simvastatin-decreased cell viability was restored in the presence of pifithrin, a p53 inhibitor. Simvastatin induced p53 phosphorylation and acetylation in a time-dependent manner. In addition, simvastatin activated p38 mitogen-activated protein kinase (p38MAPK) and inhibitor of p38MAPK signaling abrogated simvastatin’s effects of increasing p53 and p21 promoter luciferase activity. Survivin promoter luciferase activity in the presence of simvastatin was restored by p38MAPK inhibitor. In conclusion, we report a p38MAPK-mediated downregulation of survivin and its functional correlation with p53 increased HCT116 colorectal cancer cell apoptosis in the presence of simvastatin.

並列關鍵字

Statins、Survivin、apoptosis

參考文獻

Aberg, M., M. Wickstrom, and A. Siegbahn. 2008. Simvastatin induces apoptosis in human breast cancer cells in a NFkappaB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa. Thrombosis research 122:191-202.

Altieri, D.C. 2008. New wirings in the survivin networks. Oncogene 27:6276-6284.

Ambrosini, G., C. Adida, and D.C. Altieri. 1997. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917-921.

Ashkenazi, A. 2002. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420-430.

Ashraf, N., S. Zino, A. Macintyre, D. Kingsmore, A.P. Payne, W.D. George, and P.G. Shiels. 2006. Altered sirtuin expression is associated with node-positive breast cancer. Br J Cancer 95:1056-1061.

國際替代計量

simvastatin藥物誘導人類大腸癌細胞死亡的分子機轉探討

全文下載

主題瀏覽