2010-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659349摘要：細胞自我吞噬(autophagy)是指細胞在惡劣環境下，經由吞噬細胞內物質產生能量渡過外界壓力的一種保護機制；也有研究報導指出，藥物會誘導癌細胞產生autophagy，造成細胞過度吞噬其內容物而死亡，因此，autophagy在癌細胞為保護或是引發毒殺作用，目前仍無定論。Statins 經由抑制HMG-CoA reductase 活性減少膽固醇之合成，為預防心血管疾病之臨床用藥。有研究報導指出，statins 具抗癌作用，與停止細胞週期或引發細胞凋亡相關。我們的初步結果發現，癌細胞處理statins 會引起autophagy並活化AMPK；statins 引起之autophagy現象在p21-/- cells 會消失。此外，我們也發現statins會引發ER stress。併用atorvasatin 和autophagy抑制劑bafilomycin A1 可抑制細胞生長並引發apoptosis。因此，我們將利用動物模式研究statins 引發autophagy之作用，特別是合併autophagy抑制劑的抗癌效果。3 年內我們將執行7 項目標：(1)探討statins 在各種癌細胞引發細胞自我吞噬之作用。(2)研究statins 是否透過AMPK/mTOR 調節autophagy (3)研究p21 在statins-induced autophagy之角色，特別是和AMPK之關係 (4)研究ER stress 在statins-induced autophagy之角色，特別是和p21 及AMPK之關係 (5)利用臨床肝癌及大腸癌症病人之組織分析AMPK/p21/ER stress/autophagic marker之關係 (6)研究statins 引發之autophagy 為細胞保護或是細胞死亡 (7)利用動物模式探討statins 合併autophagy抑制劑bafilomycin A1 之治癌效果。<br> Abstract: Autophagy is a physiological process involved in the turnover of proteins orintracellular organelles. It serves as a temporary survival mechanism during starvation whereself-digestion becomes an alternative energy source. Many therapeutic agents such astamoxifen, butyrate or SAHA are reported to induce autophagy to promote cell death, whichcalled autophagic cell death. Therefore, the role of autophagy on cell protection or cell deathis still controversial. Statins are HMG-CoA reductase inhibitors with importantcholesterol-lowering properties. Recent experimental evidences show that statins exhibitanticancer effects. Such properties are attributed to induction of either cell cycle arrest ofapoptosis of cancer cells. Our preliminary data found that statins induced autophagy andactivated AMPK in cancer cells. However, atorvastatin-induced autophagy did not observedin HCT116 p21-/- cells. Statins also activated ER stress responses in cancer cells.Combination of atorvastatin with bafilomycin A1 inhibited cell proliferation and inducedapoptosis. Therefore, we will investigate the roles of AMPK, p21 and ER stress instatins-induced autophagy. The effect of statins-induced autophagy in cancer therapy will befurther examined in animal model. Seven specific aims are proposed to be executed inthree years: (1) To study statins-induced autophagy in various cancer cells. (2) To elucidatethe molecular mechanism of statins-induced autophagy, especially the role of AMPK andmTOR. (3) To elucidate the molecular mechanism of statins-induced autophagy, especiallythe role of p21 and its relationship with AMPK. (4) To elucidate the molecular mechanism ofstatins-induced autophagy, especially the role of ER stress and its relationship with p21 andAMPK. (5) To investigate the correlation and expression level of AMPK, p21, ER stress andautophagy marker in clinical hepatoma and colorectal cancer patients. (6) To study the roleof statins-induced autophagy in cancer cell survival or cell death. (7) To investigate theanticancer effect of combinations of statins with bafilomycin A1 on animal models.細胞自我吞噬降血脂藥物statins肝癌大腸癌autophagystatinshepatocellular carcinoma (HCC)colorectal carcinoma (CRC)