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

  • Cell Death Dis. 2017 Oct 12;8(10):e3095. doi: 10.1038/cddis.2017.411.
Junjie Xu  1 ,  Longbo Zheng  1 ,  Jiang Chen  1 ,  Yin Sun  2 ,  Hui Lin  1 ,  Ren-An Jin  1 ,  Minyue Tang  3 ,  Xiao Liang  1 ,  Xiujun Cai  1
Affiliations
  • 1. Key Laboratory of Endoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
  • 2. Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 3. Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China.
PMID: 29022906 DOI: 10.1038/cddis.2017.411
Abstract

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.

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