https://scholars.lib.ntu.edu.tw/handle/123456789/192514
標題: | Cyclooxygenase-2 Inducing Mcl-1-Dependent Survival Mechanism in Human Lung Adenocarcinoma Cl1.0 Cells - Involvement of Phosphatidylinositol 3- Kinase/Akt Pathway | 作者: | LIN, MING-TSAN | 關鍵字: | SIGNALING PATHWAY;INDUCED APOPTOSIS;CANCER CELLS;EXPRESSION;MCL-1;GENE | 公開日期: | 2001 | 卷: | v.276 | 期: | n.52 | 起(迄)頁: | 48997-49002 | 來源出版物: | JOURNAL OF BIOLOGICAL CHEMISTRY | 摘要: | Cyclooxygenase 2 (COX-2) has been reported to be commonly expressed in advanced stages of human lung adenocarcinoma. In this study, the COX-2 constitutive expression vector was transfected into a human lung adenocarcinoma cell line CL1.0 and several clones were obtained which stably expressed COX -2. These COX-2-overexpressed clones demonstrated remarkable resistance to apoptosis induced by Ultraviolet B (UVB) irradiation, vinblastine B (VBL) cell lymphoma-2 (Bcl-2), or other anti- cancer drugs. To understand how COX-2 prevents apoptosis, the investigators examined the expression level of Bcl-2 family members. Mcl-1 , but not other Bcl-2 members, was significantly up-regulated by COX-2 transfection or prostaglandin E, (PGE(2)) treatment. Treatment of COX-2- overexpressed cells (cox-2/cl.4) with two specific COX-2 inhibitors, NS- 398 and celecoxib, caused an effective reduction of the increased level of Mcl-1. These data suggest that the expression level of Mcl-1 is tightly regulated by COX-2. Moreover, transfection of cox-2/cl.4 cells with antisense Mcl-1 enhanced apoptosis induced by UVB irradiation, revealing that Mcl-1 plays a crucial role in cell survival activity mediated by COX- 2. Furthermore, COX-2 transfection or PGE(2), treatment evidently activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Inhibition of the PI3K pathway by LY294002 or wortmannin effectively attenuated the increased level of Mcl-1 induced by COX-2 or PGE(2). Blocking the PI3K activity with a dominant-negative vector, DN-p85, also greatly diminished the level of Mcl-1 and enhanced UVB-elicited cell death in cells transfected by COX-2. In a similar way, LY294002 inhibited cell survival and Mcl-1 level in PGE(2)-treated CL1.0 cells. These findings suggest that COX-2 promotes cell survival by up- regulating the level of Mcl-1 by activating the PI3K/Akt- dependent pathway. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/96216 |
顯示於: | 醫學系 |
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