Mazzanti Roberto, Platini Francesca, Bottini Consuelo, Fantappiè Ornella, Solazzo Michela, Tessitore Luciana
2nd Medical Oncology of Azienda Ospedaliero-Universitaria Careggi, University of Florence, Istituto Toscano Tumori, Florence, Italy.
Biochem Pharmacol. 2009 Jul 1;78(1):21-32. doi: 10.1016/j.bcp.2009.03.013. Epub 2009 Mar 24.
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.
许多肿瘤对药物诱导的细胞周期阻滞和凋亡具有抗性。我们曾报道，塞来昔布可使人类多药耐药（MDR）肝癌细胞系恢复凋亡。在此我们表明，P-糖蛋白（P-gp）通过下调HGF/MET自分泌环和Bcl-2表达，介导塞来昔布在人类MDR过表达肝癌细胞系中诱导的细胞周期阻滞和自噬。细胞暴露于低浓度塞来昔布会下调mTOR表达并导致G1期阻滞和自噬，而高浓度则触发凋亡。细胞生长抑制和自噬与TGFβ1、p16（INK4b）、p21（Cip1）和p27（Kip1）表达上调以及细胞周期蛋白D1、细胞周期蛋白E、pRb和E2F表达下调相关。在转染了MDR1小干扰RNA的细胞中显示了P-糖蛋白表达在MDR细胞克隆对细胞周期阻滞、自噬和凋亡抗性中的作用。这些发现表明，P-gp的组成性表达参与了HGF/MET自分泌环，该环导致Bcl-2和mTor表达增加，抑制eIF2α表达，对自噬/凋亡产生抗性并促进细胞周期进程。由于mTor抑制剂已被提议用于治疗“耐药”癌症，这些数据可能有助于解释mTor抑制剂的逆转作用。
