Effect of RGD-disintegrins on melanoma cell growth and metastasis: involvement of the actin cytoskeleton, FAK and c-Fos.
The effects and molecular mechanisms of RGD-disintegrins isolated from snake venoms on the growth and metastatic potential of B16F10-melanoma cells were investigated. Jarastatin (JT) from Bothrops jararaca is a ligand of alpha(5)beta(1), alpha(v)beta(3) and alpha(m)beta(2) integrins, flavoridin (FL) from Trimeresurus flavoridis binds preferentially to alpha(5)beta(1) and kistrin (KR) from Calloselasma rhodostoma is a selective ligand of alpha(v)beta(3). When injected simultaneously with melanoma cells in mice, the three disintegrins significantly reduced tumor lung colonization. On the other hand, JT and FL, but not KR, inhibited B16F10 cell growth in vitro. Interaction of JT or FL with melanoma cells induced actin cytoskeleton rearrangement, increasing actin polymerization and FAK phosphorylation. The effect of FL correlates with the decrease in the constitutively high nuclear content of c-Fos, whereas JT interfered with NF-kappaB translocation in melanoma cells. None of the disintegrins produced alterations in the nuclear Erk-2. The results provide further evidence to suggest RGD-disintegrins as potent anti-metastatic agents in vivo, and indicate that their interaction with alpha(5)beta(1) integrin interfere with integrin-couple signaling, down-regulating transcription factors and negatively modulating cell proliferation. These effects may contribute to inhibition of melanoma cell invasion in vivo.
Oliva
Isabela Batista
IB
Departamento de Farmacologia, Instituto de Biologia Roberto Alcântara Gomes, Universidade do Estado do Rio de Janeiro, Av. 28 de setembro 87, 5th Floor, Vila Isabel, Rio de Janeiro 20551-030, RJ, Brazil.
Coelho
Raphael Molinaro
RM
Barcellos
Gabriel Gjorup
GG
Saldanha-Gama
Roberta
R
Wermelinger
Luciana S
LS
Marcinkiewicz
Cezary
C
Benedeta Zingali
Russolina
R
Barja-Fidalgo
Christina
C
D000199:Actins / Q000502:physiology*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000502:physiology*; D019483:Disintegrins / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*
D000199:Actins; D019483:Disintegrins; D016328:NF-kappa B; D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; C047981:arginyl-glycyl-aspartic acid; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1