ERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer

Abstract

Purpose: Up to 80% of ovarian cancer patients develop platinum-resistance over time of platinum-based chemotherapy. Increased HIF-1α level is an important mechanism governing platinum-resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF-1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF-1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer. Experimental Design: We first used a quantitative high throughput combinational screen (qHTCS) to identify novel drugs that could re-sensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF-1α (YC-1), ERK (selumetinib), and TGF-β1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGF-β1/ERK/PHD2-mediated pathway regulating HIF-1α stability in PROC was discovered. Results: YC-1 and selumetinib re-sensitized PROC cells to cisplatin. Next, the prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK. Phosphorylation of PHD2 by ERK prevents its binding to HIF-1α, thus inhibiting HIF-1α hydroxylation and degradation-increasing HIF-1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGF-β1, promoting platinum-resistance by stabilizing HIF-1α. Inhibition of TGF-β1 by SB431542, ERK by selumetinib, or HIF-1α by YC-1 efficiently overcame platinum-resistance both in vitro and in vivo. The results from clinical samples confirm activation of the ERK/PHD2/HIF-1α axis in PROC patients, correlating highly with poor prognoses for patients. Conclusions: HIF-1α stabilization is regulated by TGF-β1/ERK/PHD2 axis in PROC. Hence, inhibiting TGF-β1, ERK, or HIF-1α is potential strategy for treating PROC patients.