PMID- 26801746
OWN - NLM
STAT- MEDLINE
DCOM- 20160706
LR  - 20191210
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Print)
IS  - 0304-3835 (Linking)
VI  - 373
IP  - 1
DP  - 2016 Apr 1
TI  - Overcoming cisplatin resistance of ovarian cancer cells by targeting 
      HIF-1-regulated cancer metabolism.
PG  - 36-44
LID - S0304-3835(16)00021-5 [pii]
LID - 10.1016/j.canlet.2016.01.009 [doi]
AB  - Cisplatin is currently one of the most effective chemotherapeutic drugs used for 
      treating ovarian cancer; however, resistance to cisplatin is common. In this 
      study, we explored an experimental strategy for overcoming cisplatin resistance 
      of human ovarian cancer from the new perspective of cancer cell metabolism. By 
      using two pairs of genetically matched cisplatin-sensitive and 
      cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that 
      downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic 
      enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin 
      resistance of human ovarian cancer cells. We found that cisplatin downregulated 
      the level of the regulatable alpha subunit of HIF-1, HIF-1alpha, in cisplatin-sensitive 
      ovarian cancer cells through enhancing HIF-1alpha degradation but did not 
      downregulate HIF-1alpha in their cisplatin-resistant counterparts. Overexpression of 
      a degradation-resistant HIF-1alpha (HIF-1alpha DeltaODD) reduced cisplatin-induced apoptosis 
      in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1alpha or 
      pharmacological promotion of HIF-1alpha degradation enhanced response to cisplatin in 
      both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further 
      demonstrated that knockdown of HIF-1alpha improved the response of 
      cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic 
      glycolysis in the resistant cancer cells toward mitochondrial oxidative 
      phosphorylation, leading to cell death through overproduction of reactive oxygen 
      species. Our findings suggest that the HIF-1alpha-regulated cancer metabolism pathway 
      could be a novel target for overcoming cisplatin resistance in ovarian cancer.
CI  - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.
FAU - Ai, Zhihong
AU  - Ai Z
AD  - Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated 
      Sixth People's Hospital, Shanghai 200233, China; Department of Experimental 
      Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 
      77030, USA.
FAU - Lu, Yang
AU  - Lu Y
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA.
FAU - Qiu, Songbo
AU  - Qiu S
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA.
FAU - Fan, Zhen
AU  - Fan Z
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston, TX 77030, USA. Electronic address: zfan@mdanderson.org.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R01 CA129036/CA/NCI NIH HHS/United States
GR  - R01 CA179015/CA/NCI NIH HHS/United States
GR  - CA016672/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 - 20160119
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Isoenzymes)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 1.1.1.27.- (Lactate Dehydrogenase 5)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cisplatin/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - *Drug Resistance, Neoplasm/genetics
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Glycolysis/*drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Isoenzymes/genetics/metabolism
MH  - L-Lactate Dehydrogenase/genetics/metabolism
MH  - Lactate Dehydrogenase 5
MH  - Mitochondria/drug effects/metabolism
MH  - Ovarian Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Oxidative Phosphorylation/*drug effects
MH  - Oxidative Stress/drug effects
MH  - Proteolysis
MH  - RNA Interference
MH  - Reactive Oxygen Species/metabolism
MH  - Time Factors
MH  - Transfection
PMC - PMC4769873
MID - NIHMS752865
OTO - NOTNLM
OT  - Cancer metabolism
OT  - Cisplatin
OT  - HIF-1
OT  - Ovarian cancer
OT  - Resistance
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2016/01/24 06:00
MHDA- 2016/07/07 06:00
PMCR- 2017/04/01
CRDT- 2016/01/24 06:00
PHST- 2015/09/16 00:00 [received]
PHST- 2016/01/04 00:00 [revised]
PHST- 2016/01/06 00:00 [accepted]
PHST- 2016/01/24 06:00 [entrez]
PHST- 2016/01/24 06:00 [pubmed]
PHST- 2016/07/07 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - S0304-3835(16)00021-5 [pii]
AID - 10.1016/j.canlet.2016.01.009 [doi]
PST - ppublish
SO  - Cancer Lett. 2016 Apr 1;373(1):36-44. doi: 10.1016/j.canlet.2016.01.009. Epub 
      2016 Jan 19.