HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer

dc.citation.firstpage33705en_US
dc.citation.issueNumber32en_US
dc.citation.journalTitleOncotargeten_US
dc.citation.lastpage33719en_US
dc.citation.volumeNumber6en_US
dc.contributor.authorMondal, Susmitaen_US
dc.contributor.authorRoy, Debarshien_US
dc.contributor.authorCamacho-Pereira, Julianaen_US
dc.contributor.authorKhurana, Ashwanien_US
dc.contributor.authorChini, Eduardoen_US
dc.contributor.authorYang, Lifengen_US
dc.contributor.authorBaddour, Joelleen_US
dc.contributor.authorStilles, Katherineen_US
dc.contributor.authorPadmabandu, Sethen_US
dc.contributor.authorLeung, Samen_US
dc.contributor.authorKalloger, Steveen_US
dc.contributor.authorGilks, Blakeen_US
dc.contributor.authorLowe, Valen_US
dc.contributor.authorDierks, Thomasen_US
dc.contributor.authorHammond, Edwarden_US
dc.contributor.authorDredge, Keithen_US
dc.contributor.authorNagrath, Deepaken_US
dc.contributor.authorShridhar, Vijien_US
dc.date.accessioned2016-03-28T20:49:40Zen_US
dc.date.available2016-03-28T20:49:40Zen_US
dc.date.issued2015en_US
dc.description.abstractWarburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.en_US
dc.identifier.citationMondal, Susmita, Roy, Debarshi, Camacho-Pereira, Juliana, et al.. "HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer." <i>Oncotarget,</i> 6, no. 32 (2015) Impact Journals, LLC.: 33705-33719. http://dx.doi.org/10.18632/oncotarget.5605.en_US
dc.identifier.doihttp://dx.doi.org/10.18632/oncotarget.5605en_US
dc.identifier.urihttps://hdl.handle.net/1911/88656en_US
dc.language.isoengen_US
dc.publisherImpact Journals, LLC.en_US
dc.rightsAll content, except where otherwise noted, is licensed under aᅠCreative Commons Attribution 3.0 License.ᅠen_US
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en_US
dc.subject.keywordHB-EGFen_US
dc.subject.keywordHSulf-1en_US
dc.subject.keywordPG545en_US
dc.subject.keywordWarburg effecten_US
dc.subject.keywordc-Mycen_US
dc.subject.keywordovarian canceren_US
dc.titleHSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian canceren_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
5605-76613-3-PB.pdf
Size:
4.86 MB
Format:
Adobe Portable Document Format
Description: