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Supplementary Data from ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer

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posted on 2023-03-31, 21:31 authored by Zhuqing Li, Wei Zhou, Yi Zhang, Wei Sun, Mingo M.H. Yung, Jing Sun, Jing Li, Chi-Wei Chen, Zongzhu Li, Yunxiao Meng, Jie Chai, Yuan Zhou, Stephanie S. Liu, Annie N.Y. Cheung, Hextan Y.S. Ngan, David W. Chan, Wei Zheng, Wenge Zhu

Figure S1. Establishment of platinum-resistant ovarian cancer cell lines. Related to Figure 1. Figure S2. YC-1 targets HIF-1α signaling in PROC cells in vitro and in vivo. Related to Figure 2. Figure S3. ERK1/2 regulates HIF-1α activity in ovarian cancer cells. Related to Figure 3. Figure S4. ERK1/2 regulate HIF-1α signaling by directly interacting with and phosphorylating PHD2. Related to Figure 4. Figure S5. TGF-β1 receptor inhibitor SB431542 suppresses ERK/HIF-1α signaling. Related to Figure 5. Figure S6. TGF-β1/ERK/HIF-1α pathway activation in platinum sensitive cell lines when treated with different dosages of cisplatin. Table S1. qHTS data for IGROV CR cells

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ARTICLE ABSTRACT

Up to 80% of patients with ovarian cancer develop platinum resistance over time to platinum-based chemotherapy. Increased HIF1α level is an important mechanism governing platinum resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer. We first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFβ1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGFβ1/ERK/PHD2-mediated pathway regulating HIF1α stability in PROC was discovered. YC-1 and selumetinib resensitized 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 HIF1α, thus inhibiting HIF1α hydroxylation and degradation—increasing HIF1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGFβ1, promoting platinum resistance by stabilizing HIF1α. Inhibition of TGFβ1 by SB431542, ERK by selumetinib, or HIF1α by YC-1 efficiently overcame platinum resistance both in vitro and in vivo. The results from clinical samples confirm activation of the ERK/PHD2/HIF1α axis in patients with PROC, correlating highly with poor prognoses for patients. HIF1α stabilization is regulated by TGFβ1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFβ1, ERK, or HIF1α is potential strategy for treating patients with PROC.

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