Interaction of CCN1 with αvβ3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells.

摘要: Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P-glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered effective chemotherapeutic agent for this neoplasia. Unfortunately, mechanism expression P-gp regulated ways to inhibit function are poorly understood. Our study was carried out determine possible role CCN1 in P-pg-mediated drug on basis validated CCN1, an extracellular matrix protein, promoting chemoresistance. As expected, overexpressed VBL-resistant lines (ACHN/VBL, A498/VBL, Caki-1/VBL, Caki-2/VBL) measured enzyme-linked immunosorbent assay. We then transfected non-VBL-resistant with Ad-CCN1 observed that IC50 VBL increased about 3-5 times. Furthermore, both antibody neutralization αvβ3 integrin blockade decreased VBL, showed associated RCC. Simultaneously, enhanced triggered PI3K/Akt pathway binding integrin, shown western blot. augmented response activation pathway, could be modified PI3K inhibitor LY294002 or siRNA transfection. Therefore, targeted restraint combination administration may beneficial treatment primary metastatic