부산대학교 도서관

Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P-glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing the accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered the most effective chemotherapeutic agent for this neoplasia. Unfortunately, the mechanism by which the expression of P-gp is regulated and the ways to inhibit the function of P-gp are poorly understood. Our study was carried out to determine the possible role of CCN1 in P-pg-mediated drug resistance on the basis of the validated function of CCN1, an extracellular matrix protein, in promoting chemoresistance. As expected, CCN1 was overexpressed in VBL-resistant cell lines (ACHNVBL, A498VBL, Caki-1VBL, and Caki-2VBL) as measured by enzyme-linked immunosorbent assay. We then transfected non-VBL-resistant cell lines with Ad-CCN1 and observed that the IC50of VBL increased by about 3–5 times. Furthermore, both CCN1 antibody neutralization and v3 integrin antibody blockade decreased the IC50of VBL, which showed that CCN1 and v3 are associated with resistance to VBL in RCC. Simultaneously, the enhanced expression of CCN1 triggered the intracellular PI3KAkt pathway by binding v3 integrin, as shown by western blot. P-gp expression was augmented in response to activation of the PI3KAkt pathway, which could be modified by PI3K inhibitor LY294002 or multidrug resistance siRNA transfection. Therefore, targeted restraint of CCN1 or v3 integrin in combination with the administration of VBL may be beneficial in the treatment of primary and metastatic RCC.