Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells: Involvement of phosphatidylinositol 3-kinase/Akt pathway
Journal
Journal of Biological Chemistry
Journal Volume
276
Journal Issue
52
Pages
48997-49002
Date Issued
2001
Author(s)
Abstract
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 E2 (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 PGE2 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 PGE2. 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 PGE2-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.
SDGs
Other Subjects
Cells; Cloning; Ultraviolet radiation; Transfection; Enzymes; 2 morpholino 8 phenylchromone; celecoxib; cyclooxygenase 1; cyclooxygenase 2; DNA; n (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide; phosphatidylinositol 3 kinase inhibitor; prostaglandin E2; protein bcl 2; protein mcl 1; wortmannin; androstane derivative; antineoplastic agent; Culture Media, Serum Free; cyclooxygenase 2; DNA fragment; enzyme inhibitor; isoenzyme; MCL1 protein; oncoprotein; phosphatidylinositol 3 kinase; prostaglandin synthase; proto oncogene protein akt; Proto Oncogene Proteins; Proto Oncogene Proteins c bcl 2; proto-oncogene protein akt; tumor protein; vinblastine; apoptosis; article; cancer cell culture; cell death; cell survival; cll strain CL1.0; controlled study; enzyme assay; gene overexpression; genetic transfection; human; human cell; immunoblotting; lung adenocarcinoma; priority journal; prostaglandin synthesis inhibition; ultraviolet irradiation; adenocarcinoma; apoptosis; cell culture; culture medium; drug effect; genetics; lung tumor; metabolism; nick end labeling; pathophysiology; physiology; signal transduction; upregulation; vectors; 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Androstadienes; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Survival; Culture Media, Serum-Free; DNA Fragmentation; Enzyme Inhibitors; Human; In Situ Nick-End Labeling; Isoenzymes; Lung Neoplasms; Neoplasm Proteins; Prostaglandin-Endoperoxide Synthase; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Support, Non-U.S. Gov't; Transfection; Tumor Cells, Cultured; Up-Regulation; Vinblastine
Type
journal article