J Cancer 2021; 12(7):2041-2049. doi:10.7150/jca.52092 This issue
Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Understanding mechanisms of chemoresistance in RCC cell is important for therapy and drug development. We established cisplatin (CDDP) resistant RCC cells by treating cells with increasing concentrations of CDDP. Nodal, an important embryonic morphogen, was increased in RCC/CDDP cells. Targeted inhibition of Nodal via its siRNA or neutralization antibody restored sensitivity of RCC resistant cells to CDDP treatment. It was due to that si-Nodal can decrease expression of P-glycoprotein (P-gp, encoded by ABCB1), one important ATP-binding cassette (ABC) membrane transporter for drug efflux. si-Nodal can decrease the transcription and promoter activity of ABCB1. Mechanistically, si-Nodal can decrease the phosphorylation of p65, which can bind to the promoter of ABCB1 and then trigger its transcription. Further, CDDP treatment decreased the expression of Nodal in culture medium of RCC cells. Collectively, we found that Nodal can regulate chemoresistance of RCC cells via regulating transcription of ABCB1.
Keywords: RCC, Nodal, P-gp, transcription, p65