Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

Treatment of overnight serum-starved cells with IGF increased phosphorylation of downstream target AKT, S6 and 4EBP1 and SP fraction in ZL55, ZL34 and SDM103T2 MPM cell lines. The PI3K/mTOR inhibitor NVP-BEZ235 and PI3K inhibitor wortmannin reduced the phosphorylation of downstream target AKT, S6 and 4EBP1 and decreased the SP fraction. Chemotherapy resistance mediated by drug efflux was tested by treating the cells with mitoxantrone. NVP-BEZ235 increased mitoxantrone cytotoxicity and this effect was mimicked by fumitremorgin C, a specific ABCG2 inhibitor, although not to the same extent, indicating that ABCG2-mediated drug efflux participates to chemoresistance. The involvement of ABCG2 in drug efflux was confirmed by determination of ABCG2-mediated decrease of intracellular mitoxantrone accumulation and silencing experiments. NVP-BEZ235-mediated decrease in drug efflux was associated with a significant decrease of ABCG2 present at the cell surface in ZL55 and SDM103T2 cells. In conclusion, the PI3K pathway is playing an important role in regulating the SP phenotype in MPM cells and inhibition of this activity may contribute to a more efficient cancer treatment.