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Article: Nuclear HKII–P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer

TitleNuclear HKII–P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer
Authors
Keywordsepithelial ovarian cancer
chemoresistance
cancer metabolism
hexokinase II
P-p53 (Ser15)
Issue Date2021
PublisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/
Citation
Cancers, 2021, v. 13 n. 14, p. article no. 3399 How to Cite?
AbstractIn epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII–P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII–P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.
Persistent Identifierhttp://hdl.handle.net/10722/305937
ISSN
2021 Impact Factor: 6.575
2020 SCImago Journal Rankings: 1.818
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHan, CY-
dc.contributor.authorPatten, DA-
dc.contributor.authorKim, SL-
dc.contributor.authorLim, JJ-
dc.contributor.authorChan, DW-
dc.contributor.authorSiu, MKY-
dc.contributor.authorHan, Y-
dc.contributor.authorCarmona, E-
dc.contributor.authorParks, R-
dc.contributor.authorLee, C-
dc.contributor.authorDi, LJ-
dc.contributor.authorLu, Z-
dc.contributor.authorChan, KKL-
dc.contributor.authorKu, JL-
dc.contributor.authorMacdonald, EA-
dc.contributor.authorVanderhyden, BC-
dc.contributor.authorMes-Masson, AM-
dc.contributor.authorNgan, HYS-
dc.contributor.authorCheung, ANY-
dc.contributor.authorSong, YS-
dc.contributor.authorBast, RC-
dc.contributor.authorHarper, ME-
dc.contributor.authorTsang, BK-
dc.date.accessioned2021-10-20T10:16:28Z-
dc.date.available2021-10-20T10:16:28Z-
dc.date.issued2021-
dc.identifier.citationCancers, 2021, v. 13 n. 14, p. article no. 3399-
dc.identifier.issn2072-6694-
dc.identifier.urihttp://hdl.handle.net/10722/305937-
dc.description.abstractIn epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII–P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII–P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.-
dc.languageeng-
dc.publisherMDPI AG. The Journal's web site is located at http://www.mdpi.com/journal/cancers/-
dc.relation.ispartofCancers-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectepithelial ovarian cancer-
dc.subjectchemoresistance-
dc.subjectcancer metabolism-
dc.subjecthexokinase II-
dc.subjectP-p53 (Ser15)-
dc.titleNuclear HKII–P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer-
dc.typeArticle-
dc.identifier.emailSiu, MKY: mkysiu@hku.hk-
dc.identifier.emailChan, KKL: kklchan@hkucc.hku.hk-
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.authorityChan, DW=rp00543-
dc.identifier.authoritySiu, MKY=rp00275-
dc.identifier.authorityChan, KKL=rp00499-
dc.identifier.authorityNgan, HYS=rp00346-
dc.identifier.authorityCheung, ANY=rp00542-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.3390/cancers13143399-
dc.identifier.pmid34298618-
dc.identifier.pmcidPMC8306240-
dc.identifier.scopuseid_2-s2.0-85109097938-
dc.identifier.hkuros327493-
dc.identifier.volume13-
dc.identifier.issue14-
dc.identifier.spagearticle no. 3399-
dc.identifier.epagearticle no. 3399-
dc.identifier.isiWOS:000676840000001-
dc.publisher.placeSwitzerland-

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