Ligand-mimetic anti-αIIbβ3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells

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Abstract

β3 integrin expression is the hallmark of melanoma and may serve as a potential therapeutic target. While αvβ3 integrin expression seems to be constitutive in melanoma, ectopic expression of platelet-αIIbβ3 is dependent on progression. B16a murine melanoma is a suitable model for studies on αIIbβ3 treatment strategies since αvβ3 is not expressed in this cell line. Here we have used a ligand-mimetic anti-αIIbβ3 monoclonal antibody, PAC-1, to test the biological consequences of αIIbβ3 modulation in melanoma cells. We have previously reported that in B16a cells FAK is constitutively active and tyrosine-phosphorylated. Upon PAC-1 binding to the surface αIIbβ3, which is in the active conformation, FAK became dephosphorylated through a process of PKC-dependent phosphatase activation. Furthermore, PAC-1 binding to B16a cells induced a significant decrease in phosphotyrosine-positive melanoma cells within 30 min. Treatment of B16a cells in vitro with PAC-1 significantly inhibited proliferation by decreasing the mitotic index but not affecting apoptotic rate. Incubation of B16a cells with PAC-1 decreased their lung colonization potential, suggesting a profound alteration in their biological behavior under the effect of this antibody. These preclinical data suggest that the ectopic expression of αIIbβ3 in melanoma cells can be exploited as a novel target of antibody therapy of melanoma.

Original languageEnglish
Pages (from-to)218-223
Number of pages6
JournalPathology and Oncology Research
Volume11
Issue number4
DOIs
Publication statusPublished - Jan 1 2005

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Keywords

  • Integrin
  • Ligand-mimetic
  • Melanoma
  • αIIbβ3

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Oncology
  • Cancer Research

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