RASSF6-mediated inhibition of Mcl-1 through JNK activation improves the anti-tumor effects of sorafenib in renal cell carcinoma
RASSF6-mediated inhibition of Mcl-1 through JNK activation improves the anti-tumor effects of sorafenib in renal cell carcinoma
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RASSF6介导的JNK激活抑制Mcl-1可改善索拉非尼对肾细胞癌的抗肿瘤作用
DOI：
10.1016/j.canlet.2018.05.048
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Yuan, Ya-Wei
中科院分区：
文献类型：
--
作者：
Liang, Ying-Ying;Deng, Xu-Bin;Yuan, Ya-Wei
Ras相关结构域家族成员6（RASSF6）已被证明在肾细胞癌（RCC）中可作为一种肿瘤抑制因子以及预后不良的预测因子。然而，关于RASSF6对索拉非尼耐药性的影响及其潜在机制知之甚少。在此，我们表明RASSF6的表达与肾细胞癌细胞和人体样本中的索拉非尼敏感性呈正相关。在肾细胞癌细胞系中稳定异位过表达RASSF6可降低体外和体内对索拉非尼的耐药性。在分子水平上，RASSF6激活JNK信号通路，这进一步有助于抑制Mcl - 1。抑制JNK通路可部分恢复Mcl - 1的表达和索拉非尼耐药性。总之，这些研究结果表明RASSF6通过JNK依赖性途径抑制Mcl - 1从而抑制索拉非尼耐药性。RASSF6可能作为肾细胞癌中索拉非尼治疗的一种新型调节因子。
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.