RASSF6-mediated inhibition of Mcl-1 through JNK activation improves the anti-tumor effects of sorafenib in renal cell carcinoma

Ras association domain family member 6 (RASSF6) has been shown to act as a tumor suppressor and predictor of poor prognosis in renal cell carcinoma (RCC). However, little is known about the effects of RASSF6 on sorafenib resistance or the underlying mechanism. Here, we show that RASSF6 expression positively correlates with sorafenib sensitivity in RCC cells and human samples. Stable ectopic overexpression of RASSF6 in RCC cell lines reduces resistance to sorafenib in vitro and in vivo. At a molecular level, RASSF6 activates the JNK signaling pathway, which further contributes to Mcl-1 inhibition. Suppression of the JNK pathway can partially restore Mcl-1 expression and sorafenib resistance. Together, these findings suggest that RASSF6 inhibits sorafenib resistance by repressing Mcl-1 through the JNK-dependent pathway. RASSF6 may serve as a novel regulator for sorafenib therapy in RCC.