Src-family kinase inhibitors block early steps of caveolin-1-enhanced lung metastasis by melanoma cells
Author
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Ortiz, Rina
Author
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Díaz, Jorge
Author
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Díaz Valdivia, Natalia
Author
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Martínez Meza, Samuel
Author
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Simón, Layla
Author
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Contreras Orellana, Pamela
Author
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Lobos González, Lorena
Author
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Guerrero, Simón
Author
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Leyton Campos, Lisette
Author
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Quest, Andrew F. G.
Admission date
dc.date.accessioned
2020-08-22T21:38:02Z
Available date
dc.date.available
2020-08-22T21:38:02Z
Publication date
dc.date.issued
2020
Cita de ítem
dc.identifier.citation
Biochemical Pharmacology 177 (2020) 113941
es_ES
Identifier
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10.1016/j.bcp.2020.113941
Identifier
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https://repositorio.uchile.cl/handle/2250/176518
Abstract
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In advanced stages of cancer disease, caveolin-1 (CAV1) expression increases and correlates with increased migratory and invasive capacity of the respective tumor cells. Previous findings from our laboratory revealed that specific ECM-integrin interactions and tyrosine-14 phosphorylation of CAV1 are required for CAV1-enhanced melanoma cell migration, invasion and metastasis in vivo. In this context, CAV1 phosphorylation on tyrosine-14 mediated by non-receptor Src-family tyrosine kinases seems to be important; however, the effect of Src-family kinase inhibitors on CAV1-enhanced metastasis in vivo has not been studied. Here, we evaluated the effect of CAV1 and c-Abl overexpression, as well as the use of the Src-family kinase inhibitors, PP2 and dasatinib (more specific for Src/Abl) in lung metastasis of B16F10 melanoma cells. Overexpression of CAV1 and c-Abl enhanced CAV1 phosphorylation and the metastatic potential of the B16F10 murine melanoma cells. Alternatively, treatment with PP2 or dasatinib for 2 h reduced CAV1 tyrosine-14 phosphorylation and levels recovered fully within 12 h of removing the inhibitors. Nonetheless, pre-treatment of cells with these inhibitors for 2 h sufficed to prevent migration, invasion and trans-endothelial migration in vitro. Importantly, the transient decrease in CAV1 phosphorylation by these kinase inhibitors prevented early steps of CAV1-enhanced lung metastasis by B16F10 melanoma cells injected into the tail vein of mice. In conclusion, this study underscores the relevance of CAV1 tyrosine-14 phosphorylation by Src-family kinases during the first steps of the metastatic sequence promoted by CAV1. These findings open up potential options for treatment of metastatic tumors in patients in which Src-family kinase activation and CAV1 overexpression favor dissemination of cancer cells to secondary sites.
es_ES
Patrocinador
dc.description.sponsorship
CONICYT PAI CONVOCATORIA NACIONAL SUBVENCIÓN A INSTALACIÓN EN LA ACADEMIA CONVOCATORIA ANO 2018
PAI77180019
Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)
CONICYT FONDAP
15130011
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT
1130250
1170925
1150744
1200836
1140907
11140204
Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)
CONICYT PIA/ANILLOS
1111
CONICYT PhD fellowships
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
BASAL CCTE-PFB16