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

Mondal S, Roy D, Camacho-Pereira J, Khurana A, Chini E, Yang L, Baddour J, Stilles K, Padmabandu S, Leung S, Kalloger S, et al. (2015)
ONCOTARGET 6(32): 33705-33719.

Download
Es wurde kein Volltext hochgeladen. Nur Publikationsnachweis!
Zeitschriftenaufsatz | Veröffentlicht | Englisch
Autor
; ; ; ; ; ; ; ; ; ; ;
Alle
Abstract / Bemerkung
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.
Erscheinungsjahr
Zeitschriftentitel
ONCOTARGET
Band
6
Zeitschriftennummer
32
Seite
33705-33719
ISSN
PUB-ID

Zitieren

Mondal S, Roy D, Camacho-Pereira J, et al. HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. ONCOTARGET. 2015;6(32):33705-33719.
Mondal, S., Roy, D., Camacho-Pereira, J., Khurana, A., Chini, E., Yang, L., Baddour, J., et al. (2015). HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. ONCOTARGET, 6(32), 33705-33719.
Mondal, S., Roy, D., Camacho-Pereira, J., Khurana, A., Chini, E., Yang, L., Baddour, J., Stilles, K., Padmabandu, S., Leung, S., et al. (2015). HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. ONCOTARGET 6, 33705-33719.
Mondal, S., et al., 2015. HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. ONCOTARGET, 6(32), p 33705-33719.
S. Mondal, et al., “HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer”, ONCOTARGET, vol. 6, 2015, pp. 33705-33719.
Mondal, S., Roy, D., Camacho-Pereira, J., Khurana, A., Chini, E., 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.: HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer. ONCOTARGET. 6, 33705-33719 (2015).
Mondal, 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, and Shridhar, Viji. “HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer”. ONCOTARGET 6.32 (2015): 33705-33719.

12 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.
Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S, Kalogera E, Staub J, Wang Y, Xuyang W, Khurana A, Chien J, Telang S, Chesney J, Tapolsky G, Petras D, Shridhar V., Int J Cancer 144(1), 2019
PMID: 30226266
Sulfatase-1 knockdown promotes in vitro and in vivo aggressive behavior of murine hepatocarcinoma Hca-P cells through up-regulation of mesothelin.
Mahmoud SA, Ibrahim MM, Musa AH, Huang Y, Zhang J, Wang J, Wei Y, Wang L, Zhou S, Xin B, Xuan W, Tang J., J Cell Commun Signal 12(3), 2018
PMID: 29275459
A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours.
Dredge K, Brennan TV, Hammond E, Lickliter JD, Lin L, Bampton D, Handley P, Lankesheer F, Morrish G, Yang Y, Brown MP, Millward M., Br J Cancer 118(8), 2018
PMID: 29531325
Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors.
Hammond E, Haynes NM, Cullinane C, Brennan TV, Bampton D, Handley P, Karoli T, Lanksheer F, Lin L, Yang Y, Dredge K., J Immunother Cancer 6(1), 2018
PMID: 29898788
Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer.
Nayak AP, Kapur A, Barroilhet L, Patankar MS., Cancers (Basel) 10(9), 2018
PMID: 30231564
Metformin reduces glycometabolism of papillary thyroid carcinoma in vitro and in vivo.
Shen CT, Wei WJ, Qiu ZL, Song HJ, Zhang XY, Sun ZK, Luo QY., J Mol Endocrinol 58(1), 2017
PMID: 27920093
Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.
Roy D, Mondal S, Khurana A, Jung DB, Hoffmann R, He X, Kalogera E, Dierks T, Hammond E, Dredge K, Shridhar V., Sci Rep 7(), 2017
PMID: 28169314
Metabolic Perturbation and Potential Markers in Patients with Esophageal Cancer.
Zhu X, Wang K, Liu G, Wang Y, Xu J, Liu L, Li M, Shi J, Aa J, Yu L., Gastroenterol Res Pract 2017(), 2017
PMID: 28512469
The sweet trap in tumors: aerobic glycolysis and potential targets for therapy.
Yu L, Chen X, Wang L, Chen S., Oncotarget 7(25), 2016
PMID: 26918353
Disruption of the EZH2/miRNA/β-catenin signaling suppresses aerobic glycolysis in glioma.
Wang Y, Wang M, Wei W, Han D, Chen X, Hu Q, Yu T, Liu N, You Y, Zhang J., Oncotarget 7(31), 2016
PMID: 27385092
Mechanisms of heparanase inhibitors in cancer therapy.
Heyman B, Yang Y., Exp Hematol 44(11), 2016
PMID: 27576132

41 References

Daten bereitgestellt von Europe PubMed Central.

The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches.
De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N., Expert Opin. Ther. Targets 16 Suppl 2(), 2012
PMID: 22443084
Tumor suppressors and cell metabolism: a recipe for cancer growth.
Jones RG, Thompson CB., Genes Dev. 23(5), 2009
PMID: 19270154
Heparan sulfate domain organization and sulfation modulate FGF-induced cell signaling.
Jastrebova N, Vanwildemeersch M, Lindahl U, Spillmann D., J. Biol. Chem. 285(35), 2010
PMID: 20576609
VEGF165-binding sites within heparan sulfate encompass two highly sulfated domains and can be liberated by K5 lyase.
Robinson CJ, Mulloy B, Gallagher JT, Stringer SE., J. Biol. Chem. 281(3), 2005
PMID: 16258170
Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer.
Lai J, Chien J, Staub J, Avula R, Greene EL, Matthews TA, Smith DI, Kaufmann SH, Roberts LR, Shridhar V., J. Biol. Chem. 278(25), 2003
PMID: 12686563
Characterization of the heparin-binding properties of IL-6.
Mummery RS, Rider CC., J. Immunol. 165(10), 2000
PMID: 11067924
Characterization of the interaction of interleukin-8 with hyaluronan, chondroitin sulfate, dermatan sulfate and their sulfated derivatives by spectroscopy and molecular modeling.
Pichert A, Samsonov SA, Theisgen S, Thomas L, Baumann L, Schiller J, Beck-Sickinger AG, Huster D, Pisabarro MT., Glycobiology 22(1), 2011
PMID: 21873605
Molecular diversity of heparan sulfate.
Esko JD, Lindahl U., J. Clin. Invest. 108(2), 2001
PMID: 11457867
Regulation of HSulf-1 expression by variant hepatic nuclear factor 1 in ovarian cancer.
Liu P, Khurana A, Rattan R, He X, Kalloger S, Dowdy S, Gilks B, Shridhar V., Cancer Res. 69(11), 2009
PMID: 19487294
HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma.
Lai JP, Chien J, Strome SE, Staub J, Montoya DP, Greene EL, Smith DI, Roberts LR, Shridhar V., Oncogene 23(7), 2004
PMID: 14973553
Role of heparan sulfatases in ovarian and breast cancer.
Khurana A, Beleford D, He X, Chien J, Shridhar V., Am J Cancer Res 3(1), 2013
PMID: 23359864
HSulf-1 inhibits angiogenesis and tumorigenesis in vivo.
Narita K, Staub J, Chien J, Meyer K, Bauer M, Friedl A, Ramakrishnan S, Shridhar V., Cancer Res. 66(12), 2006
PMID: 16778174
Loss of HSulf-1 expression enhances autocrine signaling mediated by amphiregulin in breast cancer.
Narita K, Chien J, Mullany SA, Staub J, Qian X, Lingle WL, Shridhar V., J. Biol. Chem. 282(19), 2007
PMID: 17363371
HSulf-1 modulates FGF2- and hypoxia-mediated migration and invasion of breast cancer cells.
Khurana A, Liu P, Mellone P, Lorenzon L, Vincenzi B, Datta K, Yang B, Linhardt RJ, Lingle W, Chien J, Baldi A, Shridhar V., Cancer Res. 71(6), 2011
PMID: 21266348
Loss of HSulf-1 expression enhances tumorigenicity by inhibiting Bim expression in ovarian cancer.
He X, Khurana A, Roy D, Kaufmann S, Shridhar V., Int. J. Cancer 135(8), 2014
PMID: 24596063
Sulfatase 1 (hSulf-1) reverses basic fibroblast growth factor-stimulated signaling and inhibits growth of hepatocellular carcinoma in animal model.
Xu G, Ji W, Su Y, Xu Y, Yan Y, Shen S, Li X, Sun B, Qian H, Chen L, Fu X, Wu M, Su C., Oncotarget 5(13), 2014
PMID: 24970807
HSulf-1 suppresses cell growth and down-regulates Hedgehog signaling in human gastric cancer cells.
Ma HY, Zhang F, Li J, Mo ML, Chen Z, Liu L, Zhou HM, Sheng Q., Oncol Lett 2(6), 2011
PMID: 22848304
Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.
Roy D, Mondal S, Wang C, He X, Khurana A, Giri S, Hoffmann R, Jung DB, Kim SH, Chini EN, Periera JC, Folmes CD, Mariani A, Dowdy SC, Bakkum-Gamez JN, Riska SM, Oberg AL, Karoly ED, Bell LN, Chien J, Shridhar V., Cancer Metab 2(), 2014
PMID: 25225614
PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.
Winterhoff B, Freyer L, Hammond E, Giri S, Mondal S, Roy D, Teoman A, Mullany SA, Hoffmann R, von Bismarck A, Chien J, Block MS, Millward M, Bampton D, Dredge K, Shridhar V., Eur. J. Cancer 51(7), 2015
PMID: 25754234
PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer.
Wigfield SM, Winter SC, Giatromanolaki A, Taylor J, Koukourakis ML, Harris AL., Br. J. Cancer 98(12), 2008
PMID: 18542064
Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells.
Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, Armistead S, Lemire K, Orrell J, Teich J, Chomicz S, Ferrick DA., Am. J. Physiol., Cell Physiol. 292(1), 2006
PMID: 16971499
Tumor cell metabolism: cancer's Achilles' heel.
Kroemer G, Pouyssegur J., Cancer Cell 13(6), 2008
PMID: 18538731
Understanding the Warburg effect: the metabolic requirements of cell proliferation.
Vander Heiden MG, Cantley LC, Thompson CB., Science 324(5930), 2009
PMID: 19460998
Oxidative phosphorylation enzymes in normal and neoplastic cell growth.
Capuano F, Guerrieri F, Papa S., J. Bioenerg. Biomembr. 29(4), 1997
PMID: 9387098
Signaling in control of cell growth and metabolism.
Ward PS, Thompson CB., Cold Spring Harb Perspect Biol 4(7), 2012
PMID: 22687276
c-Myc and cancer metabolism.
Miller DM, Thomas SD, Islam A, Muench D, Sedoris K., Clin. Cancer Res. 18(20), 2012
PMID: 23071356
Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells.
Uttamsingh S, Bao X, Nguyen KT, Bhanot M, Gong J, Chan JL, Liu F, Chu TT, Wang LH., Oncogene 27(18), 2007
PMID: 17982486
PC3 is a cell line characteristic of prostatic small cell carcinoma.
Tai S, Sun Y, Squires JM, Zhang H, Oh WK, Liang CZ, Huang J., Prostate 71(15), 2011
PMID: 21432867
Heparan sulfate 6-O-endosulfatases: discrete in vivo activities and functional co-operativity.
Lamanna WC, Baldwin RJ, Padva M, Kalus I, Ten Dam G, van Kuppevelt TH, Gallagher JT, von Figura K, Dierks T, Merry CL., Biochem. J. 400(1), 2006
PMID: 16901266
Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.
Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, Armaiz-Pena G, Jiang D, Achreja A, Win J, Roopaimoole R, Rodriguez-Aguayo C, Mercado-Uribe I, Lopez-Berestein G, Liu J, Tsukamoto T, Sood AK, Ram PT, Nagrath D., Mol. Syst. Biol. 10(), 2014
PMID: 24799285
Metabolomics for mitochondrial and cancer studies.
Nagrath D, Caneba C, Karedath T, Bellance N., Biochim. Biophys. Acta 1807(6), 2011
PMID: 21420931

Export

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®

Quellen

PMID: 26378042
PubMed | Europe PMC

Suchen in

Google Scholar