Down-regulation of Fatty Acid Synthase is Associated with Decreased Akt Activation in Lovastatin Induced Apoptosis Cells

Lovaststin在誘發凋亡細胞中表現降低的脂肪酸合成酶與AKT活化作用

張源清(Yuan-Ching Chang) ； 黃彥華(Yen-Hua Huang) ； 施純明(Chwen-Ming Shih) ； 吳瑞裕(Jui-Yu Wu) ； 劉建良(Chien-Liang Liu) ； 王淑慧(Shwu-Huey Wang) ； 林俊茂(Chun-Mao Lin)

《藥物食品分析》 14卷4期 (2006/12) Pp. 340-345

摘要

脂肪酸合成酶之蛋白質表現的增加與癌症之發展呈現正相關關係，因此脂肪酸合成酶抑制作用提供了發展抗癌藥物的新目標。Lovastatin是紅麴菌Monascus purourous發酵產物的活性成分。在許多的癌細胞中，Lovastatin可抑制細胞分裂並誘發細胞凋亡。本報告揭露Lovastatin透過抑制脂肪酸合成酶的作用達到癌症化學預防的功效。以Lovastatin處理HL-60細胞，可誘發細胞凋亡。以流式細胞儀偵測次G1峰值為49.83%相對於控制組為10.43%，且可觀察到皰狀細胞膜形態及細胞核緊縮。以50 μM Lovastatin處理HepG2細胞4小時，細胞三酸甘油酯、膽固醇及脂肪酸含量分別下降到控制組中含量的79%、81%及75%。若分別以0、10、20及50 μM Lovastatin處理細胞，脂肪酸合成酶的相對蛋白質量分別為1.00、0.89、0.72及0.31。其Akt磷酸化程度顯現濃度依賴方式的下降。以反轉錄聚合酶鏈反應技術，分析Lovastatin處理過的HepG2細胞之RNA表現，顯示Lovastatin可活化Peroxisome Proliferator-Activated Receptor-gamma的RNA表現，並且抑制Sterol-regulatory element binding protein-1的RNA表現。此一結果首度揭露了Lovastatin降低脂肪酸合成酶的表現功效與脂肪酸合成酶上游調節者－Akt磷酸化活化的抑制作用具有關聯性。

關鍵字

脂肪酸合成酶 ； 洛婓史達汀 ； 史達汀 ； AKT ； PKB ； PPAR ； SREBP

並列摘要

Increased fatty acid synthase (FAS) protein expression is coordinated with cancer development. FAS inhibitors become a focus of anticancer drug development. Lovastatin, one of the active ingredients in red yeast rice, is a product of Monascus purpureus. Lovastatin has been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. This report shows that chemopreventive effects of lovastatin may be through the down regulation of FAS. Lovastatin exhibited significant apoptosis-inducing activity in HL-60 cells, as observed by flow cytometry (with 49.83% in sub-G1 peak compared to the control, 10.43%), blebbing cell membrane morphology, and nuclear condensation. Cellular triglyceride, cholesterol, and free fatty acid in HepG2 cells were reduced to 79%, 81%, and 75%, respectively, upon lovastatin treatment (50 μM) for 4 h. The relative levels of FAS protein after treatment with 0, 10, 20, and 50 μM lovastatin were 1.00, 0.89, 0.72, and 0.31, respectively. Phosphorylated Akt was reduced in a dose-dependent manner. Reverse transcription PCR analysis showed that lovastatin upregulated PPAR-γ and inhibited SREBP-1 mRNA expression in HepG2 cells. Our current results implicate that lovastatin inhibiting FAS expression is associated with the decreased Akt activation.

並列關鍵字

fatty acid synthase ； lovastatin ； PKB/Akt ； PPAR ； statin ； SREBP