Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line |
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Authors: | Roberto Mazzanti,Francesca Platini,Ornella Fantappiè ,Luciana Tessitore |
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Affiliation: | a 2nd Medical Oncology of Azienda Ospedaliero-Universitaria Careggi, University of Florence, Istituto Toscano Tumori, Florence, Italy b Department of Food, Chemical, Pharmaceutical and Pharmacological Sciences (DISCAFF), University of East Piedmont “A. Avogadro”, Novara, Italy |
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Abstract: | 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-glycoprotein (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, p16INK4b, p21Cip1 and p27Kip1 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 MDR1 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. |
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Keywords: | MDR Celecoxib P-gp HGF/MET Autophagy |
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