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

TitleERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer
Authors
Issue Date2019
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/
Citation
Clinical Cancer Research, 2019, Epub How to Cite?
AbstractPurpose: 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.
Persistent Identifierhttp://hdl.handle.net/10722/272379
ISSN
2017 Impact Factor: 10.199
2015 SCImago Journal Rankings: 5.314

 

DC FieldValueLanguage
dc.contributor.authorLi, Z-
dc.contributor.authorZhou, W-
dc.contributor.authorZhang, Y-
dc.contributor.authorSun, W-
dc.contributor.authorYung, MH-
dc.contributor.authorSun, J-
dc.contributor.authorLi, J-
dc.contributor.authorChen, CW-
dc.contributor.authorLi, Z-
dc.contributor.authorMeng, Y-
dc.contributor.authorChai, J-
dc.contributor.authorZhou, Y-
dc.contributor.authorLiu, S-
dc.contributor.authorCheung, ANY-
dc.contributor.authorNgan, HYS-
dc.contributor.authorChan, DW-
dc.contributor.authorZheng, W-
dc.contributor.authorZhu, W-
dc.date.accessioned2019-07-20T10:41:09Z-
dc.date.available2019-07-20T10:41:09Z-
dc.date.issued2019-
dc.identifier.citationClinical Cancer Research, 2019, Epub-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/272379-
dc.description.abstractPurpose: 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.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/-
dc.relation.ispartofClinical Cancer Research-
dc.titleERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer-
dc.typeArticle-
dc.identifier.emailYung, MH: mhyung@hku.hk-
dc.identifier.emailLiu, S: stephasl@hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.emailChan, DW: dwchan@hku.hk-
dc.identifier.authorityLiu, S=rp00372-
dc.identifier.authorityCheung, ANY=rp00542-
dc.identifier.authorityNgan, HYS=rp00346-
dc.identifier.authorityChan, DW=rp00543-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-18-4145-
dc.identifier.hkuros298949-
dc.identifier.spageclincanres.4145.2018-
dc.identifier.epageclincanres.4145.2018-
dc.publisher.placeUnited States-

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