Down-regulation of the HGF/MET autocrine loop induced by celecoxib and mediated by P-gp in MDR-positive human hepatocellular carcinoma cell line.
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 TGFbeta1, p16(INK4b), p21(Cip1) and p27(Kip1) 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 eIF2alpha 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.
Mazzanti
Roberto
R
2nd Medical Oncology of Azienda Ospedaliero-Universitaria Careggi, University of Florence, Istituto Toscano Tumori, Florence, Italy. mazzanti-lab@dmi.unifi.it
Platini
Francesca
F
Bottini
Consuelo
C
Fantappiè
Ornella
O
Solazzo
Michela
M
Tessitore
Luciana
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D016193:G1 Phase; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016861:Cyclooxygenase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D013449:Sulfonamides; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017228:Hepatocyte Growth Factor; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D000068579:Celecoxib