title: Interaction of CCN1 with αvβ3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells.
abstract: 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 (ACHN/VBL, A498/VBL, Caki-1/VBL, and Caki-2/VBL) as measured by enzyme-linked immunosorbent assay. We then transfected non-VBL-resistant cell lines with Ad-CCN1 and observed that the IC50 of VBL increased by about 3-5 times. Furthermore, both CCN1 antibody neutralization and αvβ3 integrin antibody blockade decreased the IC50 of VBL, which showed that CCN1 and αvβ3 are associated with resistance to VBL in RCC. Simultaneously, the enhanced expression of CCN1 triggered the intracellular PI3K/Akt pathway by binding αvβ3 integrin, as shown by western blot. P-gp expression was augmented in response to activation of the PI3K/Akt pathway, which could be modified by PI3K inhibitor LY294002 or multidrug resistance siRNA transfection. Therefore, targeted restraint of CCN1 or αvβ3 integrin in combination with the administration of VBL may be beneficial in the treatment of primary and metastatic RCC.
authors.affiliation: Department of Urology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an Shaanxi, People's Republic of China.
authors.forename: Qing-Zhi
authors.initials: QZ
authors.lastname: Long
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Liu
authors.forename: Yue-Feng
authors.initials: YF
authors.lastname: Du
authors.forename: Jin-Hai
authors.initials: JH
authors.lastname: Fan
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Da-Lin
authors.initials: DL
authors.lastname: He
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D014747:Vinblastine / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D039302:Integrin alphaVbeta3; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D014747:Vinblastine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt