PMID- 31285371
OWN - NLM
STAT- MEDLINE
DCOM- 20200925
LR  - 20240329
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 25
IP  - 19
DP  - 2019 Oct 1
TI  - ERK Regulates HIF1alpha-Mediated Platinum Resistance by Directly Targeting PHD2 in 
      Ovarian Cancer.
PG  - 5947-5960
LID - 10.1158/1078-0432.CCR-18-4145 [doi]
AB  - PURPOSE: Up to 80% of patients with ovarian cancer develop platinum resistance 
      over time to platinum-based chemotherapy. Increased HIF1alpha level is an important 
      mechanism governing platinum resistance in platinum-resistant ovarian cancer 
      (PROC). However, the mechanism regulating HIF1alpha stability in PROC remains largely 
      unknown. Here, we elucidate the mechanism of HIF1alpha 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 resensitize PROC 
      cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of 
      HIF1alpha (YC-1), ERK (selumetinib), and TGFbeta1 (SB431542) with platinum drugs by in 
      vitro and in vivo experiments. Moreover, a novel TGFbeta1/ERK/PHD2-mediated pathway 
      regulating HIF1alpha stability in PROC was discovered. RESULTS: 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 HIF1alpha, thus inhibiting 
      HIF1alpha hydroxylation and degradation-increasing HIF1alpha stability. Significantly, 
      ERK/PHD2 signaling in PROC cells is dependent on TGFbeta1, promoting platinum 
      resistance by stabilizing HIF1alpha. Inhibition of TGFbeta1 by SB431542, ERK by 
      selumetinib, or HIF1alpha by YC-1 efficiently overcame platinum resistance both in 
      vitro and in vivo. The results from clinical samples confirm activation of the 
      ERK/PHD2/HIF1alpha axis in patients with PROC, correlating highly with poor prognoses 
      for patients. CONCLUSIONS: HIF1alpha stabilization is regulated by TGFbeta1/ERK/PHD2 
      axis in PROC. Hence, inhibiting TGFbeta1, ERK, or HIF1alpha is potential strategy for 
      treating patients with PROC.
CI  - (c)2019 American Association for Cancer Research.
FAU - Li, Zhuqing
AU  - Li Z
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Zhou, Wei
AU  - Zhou W
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
AD  - Department of Colorectal Surgery, Sir Run Shaw Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - Zhang, Yi
AU  - Zhang Y
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Sun, Wei
AU  - Sun W
AD  - National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
FAU - Yung, Mingo M H
AU  - Yung MMH
AD  - Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University 
      of Hong Kong, Hong Kong SAR, China.
FAU - Sun, Jing
AU  - Sun J
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Li, Jing
AU  - Li J
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Chen, Chi-Wei
AU  - Chen CW
AUID- ORCID: 0000-0001-8658-055X
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Li, Zongzhu
AU  - Li Z
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Meng, Yunxiao
AU  - Meng Y
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Chai, Jie
AU  - Chai J
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Zhou, Yuan
AU  - Zhou Y
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
FAU - Liu, Stephanie S
AU  - Liu SS
AD  - Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, 
      Hong Kong SAR, China.
FAU - Cheung, Annie N Y
AU  - Cheung ANY
AD  - Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, 
      Hong Kong SAR, China.
FAU - Ngan, Hextan Y S
AU  - Ngan HYS
AUID- ORCID: 0000-0003-3945-159X
AD  - Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University 
      of Hong Kong, Hong Kong SAR, China.
FAU - Chan, David W
AU  - Chan DW
AD  - Department of Obstetrics and Gynecology, LKS Faculty of Medicine, The University 
      of Hong Kong, Hong Kong SAR, China. wz6812@gwu.edu dwchan@hku.hk 
      wzheng@mail.nih.gov.
FAU - Zheng, Wei
AU  - Zheng W
AUID- ORCID: 0000-0003-1034-0757
AD  - National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland. 
      wz6812@gwu.edu dwchan@hku.hk wzheng@mail.nih.gov.
FAU - Zhu, Wenge
AU  - Zhu W
AD  - Department of Biochemistry and Molecular Medicine, The George Washington 
      University School of Medicine and Health Sciences, Washington, District of 
      Columbia. wz6812@gwu.edu dwchan@hku.hk wzheng@mail.nih.gov.
AD  - GW Cancer Center, The George Washington University, Washington, District of 
      Columbia.
LA  - eng
GR  - R01 CA177898/CA/NCI NIH HHS/United States
GR  - R01 CA184717/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190708
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - EC 2.7.11.24 (MAPK1 protein, human)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cisplatin/*pharmacology
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/chemistry/*metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Mitogen-Activated Protein Kinase 1/genetics/*metabolism
MH  - Ovarian Neoplasms/*drug therapy/genetics/*metabolism
MH  - Transforming Growth Factor beta1/genetics/*metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC7449248
MID - NIHMS1533922
COIS- The authors declare no potential conflicts of interest.
EDAT- 2019/07/10 06:00
MHDA- 2020/09/26 06:00
PMCR- 2020/08/26
CRDT- 2019/07/10 06:00
PHST- 2018/12/18 00:00 [received]
PHST- 2019/05/18 00:00 [revised]
PHST- 2019/07/02 00:00 [accepted]
PHST- 2019/07/10 06:00 [pubmed]
PHST- 2020/09/26 06:00 [medline]
PHST- 2019/07/10 06:00 [entrez]
PHST- 2020/08/26 00:00 [pmc-release]
AID - 1078-0432.CCR-18-4145 [pii]
AID - 10.1158/1078-0432.CCR-18-4145 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2019 Oct 1;25(19):5947-5960. doi: 10.1158/1078-0432.CCR-18-4145. 
      Epub 2019 Jul 8.