Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer

Jinping Lai, Jeremy Chien, Julie Staub, Rajeswari Avula, Eddie L. Greene, Tori A. Matthews, David I. Smith, Scott H. Kaufmann, Lewis R. Roberts, Viji Shridhar

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

Emerging data suggest that signaling by heparin-binding growth factors is influenced by the sulfation state of N-acetylglucosamine residues of heparan sulfate proteoglycans (HSPGs). Here we report that the recently identified protein HSulf-1, a heparin-degrading endosulfatase, encodes a cell surface-associated enzyme that diminishes sulfation of cell surface HSPGs. The message encoding this enzyme is readily detectable in a variety of normal tissues, including normal ovarian surface epithelial cells, but is undetectable in 5 of 7 ovarian carcinoma cell lines and markedly diminished or undetectable in ∼75% of ovarian cancers. Similar down-regulation is also observed in breast, pancreatic, renal cells, and hepatocellular carcinoma lines. Re-expression of HSulf-1 in ovarian cancer cell lines resulted in diminished HSPG sulfation, diminished phosphorylation of receptor tyrosine kinases that require sulfated HSPGs as co-receptors for their cognate ligands, and diminished downstream signaling through the extracellular signal-regulated kinase pathway after treatment with fibroblast growth factor-2 or heparin-binding epidermal growth factor. Consistent with these changes, HSulf-1 re-expression resulted in reduced proliferation as well as sensitivity to induction of apoptosis by the broad spectrum kinase inhibitor staurosporine and the chemotherapeutic agent cisplatin. Collectively, these observations provide evidence that HSulf-1 modulates signaling by heparin-binding growth factors, and HSulf-1 down-regulation represents a novel mechanism by which cancer cells can enhance growth factor signaling.

Original languageEnglish (US)
Pages (from-to)23107-23117
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number25
DOIs
StatePublished - Jun 20 2003
Externally publishedYes

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Heparan Sulfate Proteoglycans
Heparin
Intercellular Signaling Peptides and Proteins
Up-Regulation
Cells
Ovarian Neoplasms
Neoplasms
Down-Regulation
Cell Line
Phosphorylation
Staurosporine
Acetylglucosamine
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
Fibroblast Growth Factor 2
Enzymes
Renal Cell Carcinoma
Epidermal Growth Factor
Cisplatin
Hepatocellular Carcinoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lai, J., Chien, J., Staub, J., Avula, R., Greene, E. L., Matthews, T. A., ... Shridhar, V. (2003). Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. Journal of Biological Chemistry, 278(25), 23107-23117. https://doi.org/10.1074/jbc.M302203200

Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. / Lai, Jinping; Chien, Jeremy; Staub, Julie; Avula, Rajeswari; Greene, Eddie L.; Matthews, Tori A.; Smith, David I.; Kaufmann, Scott H.; Roberts, Lewis R.; Shridhar, Viji.

In: Journal of Biological Chemistry, Vol. 278, No. 25, 20.06.2003, p. 23107-23117.

Research output: Contribution to journalArticle

Lai, J, Chien, J, Staub, J, Avula, R, Greene, EL, Matthews, TA, Smith, DI, Kaufmann, SH, Roberts, LR & Shridhar, V 2003, 'Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer', Journal of Biological Chemistry, vol. 278, no. 25, pp. 23107-23117. https://doi.org/10.1074/jbc.M302203200
Lai, Jinping ; Chien, Jeremy ; Staub, Julie ; Avula, Rajeswari ; Greene, Eddie L. ; Matthews, Tori A. ; Smith, David I. ; Kaufmann, Scott H. ; Roberts, Lewis R. ; Shridhar, Viji. / Loss of HSulf-1 up-regulates heparin-binding growth factor signaling in cancer. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 25. pp. 23107-23117.
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