Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer

Manolis C. Demetriou, Michael E. Pennington, Raymond B Nagle, Anne E Cress

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

During human prostate cancer progression, the integrin α6β1 (laminin receptor) is expressed on the cancer cell surface during invasion and in lymph node metastases. We previously identified a novel structural variant of the α6 integrin called α6p. This variant was produced on the cell surface and was missing the β-barrel extracellular domain. Using several different concentrations of amiloride, aminobenzamidine and PAI-1 and the urokinase-type plasminogen activator (uPA) function-blocking antibody (3689), we showed that uPA, acting as a protease, is responsible for production of α6p. We also showed that addition of uPA in the culture media of cells that do not produce α6p, resulted in a dose-dependent α6p production. In contrast, the addition of uPA did not result in the cleavage of other integrins. Using α2-antiplasmin and plasmin depleted media, we observed that uPA cleaves the α6 integrin directly. Further, 12-o-tetradecanoyl-phorbol-13-acetate (TPA) induced the production of α6p, and this induction was abolished by PAI-1 but not α2-antiplasmin. Finally, the α6p integrin variant was detected in invasive human prostate carcinoma tissue indicating that this is not a tissue culture phenomenon. These data, taken together, suggest that this is a novel function of uPA, that is, to remove the β-barrel ligand-binding domain of the integrin while preserving its heterodimer association.

Original languageEnglish (US)
Pages (from-to)550-558
Number of pages9
JournalExperimental Cell Research
Volume294
Issue number2
DOIs
StatePublished - Apr 1 2004

Fingerprint

Integrin alpha6
Urokinase-Type Plasminogen Activator
Integrins
Prostatic Neoplasms
Antifibrinolytic Agents
Plasminogen Activator Inhibitor 1
Laminin Receptors
Blocking Antibodies
Amiloride
Fibrinolysin
Culture Media
Prostate
Acetates
Peptide Hydrolases
Lymph Nodes
Neoplasm Metastasis
Ligands
Carcinoma

Keywords

  • Integrin
  • Prostate cancer
  • Urokinase

ASJC Scopus subject areas

  • Cell Biology

Cite this

Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer. / Demetriou, Manolis C.; Pennington, Michael E.; Nagle, Raymond B; Cress, Anne E.

In: Experimental Cell Research, Vol. 294, No. 2, 01.04.2004, p. 550-558.

Research output: Contribution to journalArticle

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