Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals

作者：Junjie Xu, Longbo Zheng, Chen Jiang, Yin Sun, Hui Lin, Renan Jin, Minyue Tang, Xiao Liang, Xiujun Cai · 发表于：Cell Death and Disease · 年份：2017 · DOI：10.1038/cddis.2017.411 · 被引用次数：74 · 研究领域：Cancer, Hypoxia, and Metabolism、Hepatocellular Carcinoma Treatment and Prognosis、Cancer, Lipids, and Metabolism

Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2α, increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.