Cyclophilin D-mediated apoptosis attributes to sorafenib-induced cytotoxicity in clear cell-renal cell carcinoma.

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.