Ligand-mimetic anti-alphaIIb beta3 antibody PAC-1 inhibits tyrosine signaling, proliferation and lung colonization of melanoma cells.
Beta3 integrin expression is the hallmark of melanoma and may serve as a potential therapeutic target. While alphav beta3 integrin expression seems to be constitutive in melanoma, ectopic expression of platelet-alphaIIb beta3 is dependent on progression. B16a murine melanoma is a suitable model for studies on alphaIIb beta3 treatment strategies since alphav beta3 is not expressed in this cell line. Here we have used a ligand-mimetic anti-alphaIIb beta3 monoclonal antibody, PAC-1, to test the biological consequences of alphaIIb beta3 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 alphaIIb beta3, 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 alphaIIb beta3 in melanoma cells can be exploited as a novel target of antibody therapy of melanoma.
Rásó
Erzsébet
E
Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary.
Tóvári
József
J
Ladányi
Andrea
A
Varga
Norbert
N
Tímár
József
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008938:Mitosis; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine