PT - JOURNAL ARTICLE AU - Wenjie Chen AU - Lang Bai AU - Xia Wang AU - Shanling Xu AU - Steven A Belinsky AU - Yong Lin TI - Acquired activation of the Akt/COX-2/Mcl-1 pathway renders lung cancer cells resistant to apoptosis AID - 10.1124/mol.109.061226 DP - 2009 Nov 23 TA - Molecular Pharmacology PG - mol.109.061226 4099 - http://molpharm.aspetjournals.org/content/early/2009/11/23/mol.109.061226.short 4100 - http://molpharm.aspetjournals.org/content/early/2009/11/23/mol.109.061226.full AB - 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