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- Publisher Website: 10.1158/1078-0432.CCR-18-4145
- Scopus: eid_2-s2.0-85072823686
- PMID: 31285371
- WOS: WOS:000489644500024
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Article: ERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer
Title | ERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer |
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Authors | |
Issue Date | 2019 |
Publisher | American Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/ |
Citation | Clinical Cancer Research, 2019, v. 25 n. 19, p. 5947-5960 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/272379 |
ISSN | 2023 Impact Factor: 10.0 2023 SCImago Journal Rankings: 4.623 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Li, Z | - |
dc.contributor.author | Zhou, W | - |
dc.contributor.author | Zhang, Y | - |
dc.contributor.author | Sun, W | - |
dc.contributor.author | Yung, MH | - |
dc.contributor.author | Sun, J | - |
dc.contributor.author | Li, J | - |
dc.contributor.author | Chen, CW | - |
dc.contributor.author | Li, Z | - |
dc.contributor.author | Meng, Y | - |
dc.contributor.author | Chai, J | - |
dc.contributor.author | Zhou, Y | - |
dc.contributor.author | Liu, S | - |
dc.contributor.author | Cheung, ANY | - |
dc.contributor.author | Ngan, HYS | - |
dc.contributor.author | Chan, DW | - |
dc.contributor.author | Zheng, W | - |
dc.contributor.author | Zhu, W | - |
dc.date.accessioned | 2019-07-20T10:41:09Z | - |
dc.date.available | 2019-07-20T10:41:09Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Clinical Cancer Research, 2019, v. 25 n. 19, p. 5947-5960 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.uri | http://hdl.handle.net/10722/272379 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.publisher | American Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/ | - |
dc.relation.ispartof | Clinical Cancer Research | - |
dc.title | ERK regulates HIF1α-mediated platinum resistance by directly targeting PHD2 in ovarian cancer | - |
dc.type | Article | - |
dc.identifier.email | Yung, MH: mhyung@hku.hk | - |
dc.identifier.email | Liu, S: stephasl@hku.hk | - |
dc.identifier.email | Cheung, ANY: anycheun@hkucc.hku.hk | - |
dc.identifier.email | Ngan, HYS: hysngan@hkucc.hku.hk | - |
dc.identifier.email | Chan, DW: dwchan@hku.hk | - |
dc.identifier.authority | Liu, S=rp00372 | - |
dc.identifier.authority | Cheung, ANY=rp00542 | - |
dc.identifier.authority | Ngan, HYS=rp00346 | - |
dc.identifier.authority | Chan, DW=rp00543 | - |
dc.description.nature | postprint | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-18-4145 | - |
dc.identifier.pmid | 31285371 | - |
dc.identifier.pmcid | PMC7449248 | - |
dc.identifier.scopus | eid_2-s2.0-85072823686 | - |
dc.identifier.hkuros | 298949 | - |
dc.identifier.volume | 25 | - |
dc.identifier.issue | 19 | - |
dc.identifier.spage | 5947 | - |
dc.identifier.epage | 5960 | - |
dc.identifier.isi | WOS:000489644500024 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 1078-0432 | - |