title: Cyclophilin D-mediated apoptosis attributes to sorafenib-induced cytotoxicity in clear cell-renal cell carcinoma.
abstract: Cyclophilin D (CypD) is an essential regulatory component of the mitochondrial permeability transition pore (MPTP) and mediates cell necrosis. The aim of this study was to assess the effects of the multi-target drug, sorafenib, on clear cell-renal cell carcinoma (ccRCC) necrosis by regulating CypD expression and to explore whether this effect was related to the phosphorylation of extracellular signal-regulated kinases (ERKs). We used immunohistochemical analysis to compare CypD and p-ERK expression in human ccRCC tissues (n=53) and adjacent non-cancerous tissues (ANCT, n=34). CypD expression was localized to the cytoplasm of renal tubular epithelial cells and was lower in ccRCC samples while p-ERK expression was higher in ccRCC samples. In the in vitro assay, CypD was downregulated in ccRCC cell lines 786-O and A498 as compared with HK-2 which is a normal human renal tubular epithelial cell line. Overexpression of CypD induced the apoptosis of 786-O and A498 cells. Sorafenib induced the apoptosis of 786-O cells, which was coupled with the upregulation of CypD. Cyclosporin A (CsA, the inhibitor of CypD) and CypD siRNA inhibited the effect of sorafenib on apoptosis-induced 786-O and mitochondrial membrane potential depolarization. Epidermal growth factor (EGF, the activator of ERK) and ERK overexpression inhibited the effect of sorafenib on CypD expression, apoptosis-induced 786-O and mitochondrial membrane potential depolarization. In conclusion, our results suggested that CypD may represent a new therapeutic target for the treatment of ccRCC. Sorafenib induced apoptosis in ccRCC through CypD upregulation and this effect was related to the inhibition of p-ERK.
authors.affiliation: Department of Urology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Urology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
authors.forename: Xiu-Heng
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Department of Urology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
authors.forename: Heng-Cheng
authors.initials: HC
authors.lastname: Zhu
authors.affiliation: Department of Urology, Renmin Hospital, Wuhan University, Wuhan 430060, China.
authors.forename: Sheng-Qi
authors.initials: SQ
authors.lastname: Lv
authors.affiliation: Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China. Electronic address: shakurase@163.com.
authors.forename: Xing-Huan
authors.initials: XH
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D000081406:Peptidyl-Prolyl Isomerase F; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D021983:Cyclophilins
keywords: Apoptosis; Clear cell-renal cell carcinoma (ccRCC); Cyclophilin D (CypD); Necrosis; Sorafenib (PubChem code: 216239); p-Extracellular signal-regulated kinases (p-ERK)