title: HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer.
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.
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Debarshi
authors.initials: D
authors.lastname: Roy
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA.|Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Camacho-Pereira
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Khurana
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Chini
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Joelle
authors.initials: J
authors.lastname: Baddour
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Stilles
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Padmabandu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Leung
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Kalloger
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.affiliation: Department of Nuclear Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Val
authors.initials: V
authors.lastname: Lowe
authors.affiliation: Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dierks
authors.affiliation: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors.forename: Keith
authors.initials: K
authors.lastname: Dredge
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002952:Citric Acid Cycle; D005260:Female; D006019:Glycolysis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015238:Sulfotransferases / Q000172:deficiency* / Q000378:metabolism
chemical_list: C470791:SULF1 protein, human; D015238:Sulfotransferases
keywords: HB-EGF; HSulf-1; PG545; Warburg effect; c-Myc; ovarian cancer