TY - JOUR T1 - The c-MET/PI3K Signaling is Associated with Cancer Resistance to Doxorubicin and Photodynamic Therapy by Elevating BCRP/ABCG2 Expression JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.096065 SP - mol.114.096065 AU - Kyeong-Ah Jung AU - Bo-hyun Choi AU - Mi-Kyoung Kwak Y1 - 2014/12/22 UR - http://molpharm.aspetjournals.org/content/early/2014/12/22/mol.114.096065.abstract N2 - Overexpression of BCRP/ABCG2, a xenobiotic efflux transporter, is associated with anticancer drug resistance in tumors. Proto-oncogene c-MET induces cancer cell proliferation, motility, and survival, and its aberrant activation was found to be a prognostic factor in advanced ovarian cancers. In the present study, we investigated the potential cross-resistance of doxorubicin-resistant ovarian cancer cells to the pheophorbide a (Pba)-based photodynamic therapy (PDT), and suggest c-MET and BCRP/ABCG2 overexpression as an underlying molecular mechanism. A2780DR, which was established by incubating A2780 with stepwise increasing concentrations of doxorubicin, showed low levels of cellular Pba accumulation and ROS generation, and was more resistant to PDT cytotoxicity than A2780. In a microarray analysis, BCRP/ABCG2 was found to be the only drug transporter whose expression was up-regulated in A2780DR; this increase was confirmed by western blot and immunocytochemical analyses. As functional evidence, the treatment with a BCRP/ABCG2-specific inhibitor reversed A2780DR resistance to both doxorubicin and PDT. We identified that c-MET increase is related to BCRP/ABCG2 activation. The c-MET downstream PI3K/AKT signaling was activated in A2780DR and the inhibition of PI3K/AKT or c-MET repressed resistance to doxorubicin and PDT. Finally, we showed that the pharmacological and genetic inhibition of c-MET diminished levels of BCRP/ABCG2 in A2780DR. Moreover, c-MET inhibition could repress BCRP/ABCG2 expression in breast carcinoma MDA-MB-231 and colon carcinoma HT29, resulting in sensitization to doxorubicin. Collectively, our results provide a novel link of c-MET overexpression to BCRP/ABCG2 activation, suggesting that this mechanism leads to cross-resistance to both chemotherapy and PDT. ER -