Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line

Roberto Mazzanti , Francesca Platini , Consuelo Bottini , Ornella Fantappiè , Michela Solazzo , Luciana Tessitore

Many tumors are resistant to drug-induced cell cycle arrest and apoptosis. We have reported that apoptosis can be restored in human multidrug-resistant (MDR) hepatocellular carcinoma cell lines by celecoxib. Here we show that P-gp mediates cell cycle arrest and autophagy induced by celecoxib in human MDR overexpressing hepatocellular carcinoma cell line by down-regulation of the HGF/MET autocrine loop and Bcl-2 expression. Exposure of cells to a low concentration of celecoxib down-regulated the expression of mTOR and caused G1 arrest and autophagy, while higher concentration triggered apoptosis. Cell growth inhibition and autophagy were associated with up-regulation of the expression of TGFβ1, p16, p21 and p27 and down-regulation of cyclin D1, cyclin E, pRb and E2F. The role of P-glycoprotein expression in resistance of MDR cell clone to cell cycle arrest, autophagy and apoptosis was shown in cells transfected with small interfering RNA. These findings demonstrate that the constitutive expression of P-gp is involved in the HGF/MET autocrine loop that leads to increased expression of Bcl-2 and mTor, inhibition of eIF2α expression, resistance to autophagy/apoptosis and progression in the cell cycle. Since mTor inhibitors have been proposed in treatment of “drug resistant” cancer, these data may help explain the reversing effect of mTor inhibitors.

Mots clés: MDR; celecoxib; P-gp; HGF/MET; autophagy

Roberto Mazzanti, Francesca Platini, Consuelo Bottini, Ornella Fantappiè, Michela Solazzo, et al.. Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line. Biochemical Pharmacology, 2009, 78 (1), pp.21. ⟨10.1016/j.bcp.2009.03.013⟩. ⟨hal-00493506⟩