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Article: p53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer

Titlep53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer
Authors
Keywordschemoresistance
hexokinase II
metabolism ovarian cancer
p53
Issue Date2019
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0899-1987/
Citation
Molecular Carcinogenesis, 2019, v. 58 n. 11, p. 2161-2174 How to Cite?
AbstractMetabolic reprogramming (including the Warburg effect) is a hallmark of cancer, yet the association between the altered metabolism and chemoresistance remains elusive. Hexokinase II (HKII) is a key metabolic enzyme and is upregulated in multiple cancers. In this study, we examined the impact of targeting metabolism via silencing of HKII on chemoresistance in ovarian cancer (OVCA). In addition, the regulatory molecular mechanism of tumor metabolism was examined using gain‐ and loss‐of‐function approaches in epithelial OVCA cell lines of various histological subtypes. We demonstrated that cisplatin (CDDP)‐induced p53‐mediated HKII downregulation is a determinant of chemosensitivity in OVCA. Silencing of HKII sensitized chemoresistant OVCA cells to apoptosis in a p53‐dependent manner. As a negative regulator, p53 suppressed HKII transcription by promoter binding and decreased glycolysis. Pyruvate dehydrogenase kinase‐1 (PDK1) is a key regulator of cell proliferation involved in Akt signaling axis. Our Gene Expression Profiling Interactive Analysis (GEPIA) and molecular studies also revealed that PDK1, an upstream activator strongly correlates with HKII expression and regulates its metabolic activity. Finally, we demonstrated that the clinically approved drug metformin sensitizes chemoresistant OVCA cells to CDDP via PDK1‐HKII pathway. Collectively, our data implicate that p53‐‐PDK1‐HKII axis is a central regulatory component of metabolism conferring chemoresistance in OVCA.
Persistent Identifierhttp://hdl.handle.net/10722/294198
ISSN
2023 Impact Factor: 3.0
2023 SCImago Journal Rankings: 1.034
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHan, CY-
dc.contributor.authorPatten, DA-
dc.contributor.authorLee, SG-
dc.contributor.authorParks, RJ-
dc.contributor.authorChan, DW-
dc.contributor.authorHarper, ME-
dc.contributor.authorTsang, BK-
dc.date.accessioned2020-11-23T08:27:49Z-
dc.date.available2020-11-23T08:27:49Z-
dc.date.issued2019-
dc.identifier.citationMolecular Carcinogenesis, 2019, v. 58 n. 11, p. 2161-2174-
dc.identifier.issn0899-1987-
dc.identifier.urihttp://hdl.handle.net/10722/294198-
dc.description.abstractMetabolic reprogramming (including the Warburg effect) is a hallmark of cancer, yet the association between the altered metabolism and chemoresistance remains elusive. Hexokinase II (HKII) is a key metabolic enzyme and is upregulated in multiple cancers. In this study, we examined the impact of targeting metabolism via silencing of HKII on chemoresistance in ovarian cancer (OVCA). In addition, the regulatory molecular mechanism of tumor metabolism was examined using gain‐ and loss‐of‐function approaches in epithelial OVCA cell lines of various histological subtypes. We demonstrated that cisplatin (CDDP)‐induced p53‐mediated HKII downregulation is a determinant of chemosensitivity in OVCA. Silencing of HKII sensitized chemoresistant OVCA cells to apoptosis in a p53‐dependent manner. As a negative regulator, p53 suppressed HKII transcription by promoter binding and decreased glycolysis. Pyruvate dehydrogenase kinase‐1 (PDK1) is a key regulator of cell proliferation involved in Akt signaling axis. Our Gene Expression Profiling Interactive Analysis (GEPIA) and molecular studies also revealed that PDK1, an upstream activator strongly correlates with HKII expression and regulates its metabolic activity. Finally, we demonstrated that the clinically approved drug metformin sensitizes chemoresistant OVCA cells to CDDP via PDK1‐HKII pathway. Collectively, our data implicate that p53‐‐PDK1‐HKII axis is a central regulatory component of metabolism conferring chemoresistance in OVCA.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.interscience.wiley.com/jpages/0899-1987/-
dc.relation.ispartofMolecular Carcinogenesis-
dc.rightsThis is the peer reviewed version of the following article: Molecular Carcinogenesis, 2019, v. 58 n. 11, p. 2161-2174, which has been published in final form at https://doi.org/10.1002/mc.23106. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectchemoresistance-
dc.subjecthexokinase II-
dc.subjectmetabolism ovarian cancer-
dc.subjectp53-
dc.titlep53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer-
dc.typeArticle-
dc.identifier.emailChan, DW: dwchan@hku.hk-
dc.identifier.authorityChan, DW=rp00543-
dc.description.naturepostprint-
dc.identifier.doi10.1002/mc.23106-
dc.identifier.pmid31486135-
dc.identifier.scopuseid_2-s2.0-85071769301-
dc.identifier.hkuros319509-
dc.identifier.volume58-
dc.identifier.issue11-
dc.identifier.spage2161-
dc.identifier.epage2174-
dc.identifier.isiWOS:000489945600020-
dc.publisher.placeUnited States-

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