Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Sunitinib has been used as the standard of treatment for first-line RCC therapy. Understanding mechanisms of sunitinib resistance in RCC cell is important for clinical therapy and drug development. We established sunitinib resistant RCC cells by treating cells with increasing concentrations of sunitinib and named resistant cells as RCC/SR. Lefty A, an important embryonic morphogen, was increased in RCC/SR cells. Targeted inhibition of Lefty via its siRNAs restored the sensitivity of renal resistant cells to sunitinib treatment. It was due to that si-Lefty can decrease the expression of interleukin-8 (IL-8) in RCC/SR cells. Knockdown of IL-8 abolished Lefty-regulated sunitinib sensitivity of RCC cells. Mechanistically, Lefty can regulate IL-8 transcription via activation of p65, one major transcription factor of IL-8. Collectively, our present revealed that Lefty A can regulate sunitinib sensitivity of RCC cells of via NF-κB/IL-8 signals. It indicated that targeted inhibition of Lefty might be a potent approach to overcome sunitinib resistance of RCC.
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