Show simple item record

dc.contributor.authorMondal, Susmita
Roy, Debarshi
Camacho-Pereira, Juliana
Khurana, Ashwani
Chini, Eduardo
Yang, Lifeng
Baddour, Joelle
Stilles, Katherine
Padmabandu, Seth
Leung, Sam
Kalloger, Steve
Gilks, Blake
Lowe, Val
Dierks, Thomas
Hammond, Edward
Dredge, Keith
Nagrath, Deepak
Shridhar, Viji
dc.date.accessioned 2016-03-28T20:49:40Z
dc.date.available 2016-03-28T20:49:40Z
dc.date.issued 2015
dc.identifier.citation Mondal, Susmita, Roy, Debarshi, Camacho-Pereira, Juliana, et al.. "HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer." Oncotarget, 6, no. 32 (2015) Impact Journals, LLC.: 33705-33719. http://dx.doi.org/10.18632/oncotarget.5605.
dc.identifier.urihttps://hdl.handle.net/1911/88656
dc.description.abstract Warburg 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.
dc.language.iso eng
dc.publisher Impact Journals, LLC.
dc.rights All content, except where otherwise noted, is licensed under aᅠCreative Commons Attribution 3.0 License.ᅠ
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/
dc.title HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer
dc.type Journal article
dc.contributor.funder National Institutes of Health
dc.contributor.funder Mayo Clinic
dc.citation.journalTitle Oncotarget
dc.subject.keywordHB-EGF
HSulf-1
PG545
Warburg effect
c-Myc
ovarian cancer
dc.citation.volumeNumber 6
dc.citation.issueNumber 32
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.18632/oncotarget.5605
dc.identifier.pmcid PMC4741796
dc.identifier.pmid 26378042
dc.identifier.grantID P50CA136393 (National Institutes of Health)
dc.identifier.grantID CA106954 (National Institutes of Health)
dc.identifier.grantID CCaTSUL1TR000135 (Mayo Clinic)
dc.type.publication publisher version
dc.citation.firstpage 33705
dc.citation.lastpage 33719


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

All content, except where otherwise noted, is licensed under aᅠCreative Commons Attribution 3.0 License.ᅠ
Except where otherwise noted, this item's license is described as All content, except where otherwise noted, is licensed under aᅠCreative Commons Attribution 3.0 License.ᅠ