TY - JOUR T1 - Acquired activation of the Akt/COX-2/Mcl-1 pathway renders lung cancer cells resistant to apoptosis JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.061226 SP - mol.109.061226 AU - Wenjie Chen AU - Lang Bai AU - Xia Wang AU - Shanling Xu AU - Steven A Belinsky AU - Yong Lin Y1 - 2009/11/23 UR - http://molpharm.aspetjournals.org/content/early/2009/11/23/mol.109.061226.abstract N2 - Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Our previous observations demonstrated that acquired TNF-related apoptosis-inducing ligand (TRAIL)-resistance in lung cancer cells was associated with Akt-mediated stabilization of c-FLIP and Mcl-1. In this report, we determined these cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin and adriamycin, which was detected in vitro in cell cultures and in vivo in xenografted tumors. We further found that COX-2 is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 appears to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with a chemical inhibitor or reducing COX-2 protein expression level with COX-2 siRNA dramatically alleviated resistance to therapeutic-induced apoptosis. Inhibiting Akt markedly suppressed COX-2 expression, suggesting COX-2 is a downstream effector of this cell survival kinase-mediated apoptosis resistance. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppressed and knockdown of Mcl-1 substantially sensitized the cells to apoptosis. Our results establish a novel pathway that consists of Akt, COX-2, and Mcl-1 for acquired apoptosis resistance, which could be a molecular target for circumventing acquired chemoresistance in lung cancer.The American Society for Pharmacology and Experimental Therapeutics ER -