Reference | 1. Cell Death Dis. 2017 Oct 12;8(10):e3095. doi: 10.1038/cddis.2017.411. <br />
<br />
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. <br />
<br />
Xu J(1), Zheng L(1), Chen J(1), Sun Y(2), Lin H(1), Jin RA(1), Tang M(3), Liang
X(1), Cai X(1). <br />
Author information: <br />
(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. <br />
<br />
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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