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

Susmita Mondal, Debarshi Roy, Juliana Camacho-Pereira, Ashwani Khurana, Eduardo Nunes Chini, Lifeng Yang, Joelle Baddour, Katherine Stilles, Seth Padmabandu, Sam Leung, Steve Kalloger, Blake Gilks, Val Lowe, Thomas Dierks, Edward Hammond, Keith Dredge, Deepak Nagrath, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)33705-33719
Number of pages15
JournalOncotarget
Volume6
Issue number32
DOIs
StatePublished - 2015

Fingerprint

Glycolysis
Ovarian Neoplasms
Glucose
Intercellular Signaling Peptides and Proteins
Metabolomics
Enzymes
Pyruvic Acid
Oxygen Consumption
Isotopes
Biological Availability
Lactic Acid
Neoplasms
Oxidoreductases
Down-Regulation
Phosphorylation
Pharmacology
Ligands
Phenotype
Cell Line
Genes

Keywords

  • C-Myc
  • HB-EGF
  • HSulf-1
  • Ovarian cancer
  • PG545
  • Warburg effect

ASJC Scopus subject areas

  • Oncology

Cite this

HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. / Mondal, Susmita; Roy, Debarshi; Camacho-Pereira, Juliana; Khurana, Ashwani; Chini, Eduardo Nunes; 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, Vijayalakshmi.

In: Oncotarget, Vol. 6, No. 32, 2015, p. 33705-33719.

Research output: Contribution to journalArticle

Mondal, S, Roy, D, Camacho-Pereira, J, Khurana, A, Chini, EN, Yang, L, Baddour, J, Stilles, K, Padmabandu, S, Leung, S, Kalloger, S, Gilks, B, Lowe, V, Dierks, T, Hammond, E, Dredge, K, Nagrath, D & Shridhar, V 2015, 'HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer', Oncotarget, vol. 6, no. 32, pp. 33705-33719. https://doi.org/10.18632/oncotarget.5605
Mondal, Susmita ; Roy, Debarshi ; Camacho-Pereira, Juliana ; Khurana, Ashwani ; Chini, Eduardo Nunes ; 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, Vijayalakshmi. / HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. In: Oncotarget. 2015 ; Vol. 6, No. 32. pp. 33705-33719.
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AU - Roy, Debarshi

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AU - Khurana, Ashwani

AU - Chini, Eduardo Nunes

AU - Yang, Lifeng

AU - Baddour, Joelle

AU - Stilles, Katherine

AU - Padmabandu, Seth

AU - Leung, Sam

AU - Kalloger, Steve

AU - Gilks, Blake

AU - Lowe, Val

AU - Dierks, Thomas

AU - Hammond, Edward

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AU - Nagrath, Deepak

AU - Shridhar, Vijayalakshmi

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