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

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8 Citations (Scopus)

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
Publication statusPublished - 2005

Fingerprint

Tyrosine
Anti-Idiotypic Antibodies
Melanoma
Ligands
Lung
Integrins
Phosphotyrosine
Mitotic Index
Antibodies
2-carboxyarabinitol 1-phosphate
Phosphoric Monoester Hydrolases
Blood Platelets
Monoclonal Antibodies
Cell Line
Therapeutics

Keywords

  • αIIbβ3
  • Integrin
  • Ligand-mimetic
  • Melanoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pathology and Forensic Medicine

Cite this

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title = "Ligand-mimetic anti-αIIbβ3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells",
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.",
keywords = "αIIbβ3, Integrin, Ligand-mimetic, Melanoma",
author = "E. R{\'a}s{\'o} and J. T{\'o}v{\'a}ri and A. Lad{\'a}nyi and Norbert Varga and J. T{\'i}m{\'a}r",
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TY - JOUR

T1 - Ligand-mimetic anti-αIIbβ3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells

AU - Rásó, E.

AU - Tóvári, J.

AU - Ladányi, A.

AU - Varga, Norbert

AU - Tímár, J.

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

KW - αIIbβ3

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