Alternagin-C binding to α2ß1 integrin controls matrix metalloprotease-9 and matrix metalloprotease-2 in breast tumor cells and endothelial cells
J. venom. anim. toxins incl. trop. dis
;
24: 13, 2018. graf, ilus
Artículo
en Inglés
| LILACS
| ID: biblio-894171
ABSTRACT
Background:
Matrix metalloproteinases (MMPs) are key players in tumor progression, helping tumor cells to modify their microenvironment, which allows cell migration to secondary sites. The role of integrins, adhesion receptors that connect cells to the extracellular matrix, in MMP expression and activity has been previously suggested. However, the mechanisms by which integrins control MMP expression are not completely understood. Particularly, the role of α2ß1 integrin, one of the major collagen I receptors, in MMP activity and expression has not been studied. Alternagin-C (ALT-C), a glutamate-cysteine-aspartate-disintegrin from Bothrops alternatus venom, has high affinity for an α2ß1 integrin. Herein, we used ALT-C as a α2ß1 integrin ligand to study the effect of ALT-C on MMP-9 and MMP-2 expression as well as on tumor cells, fibroblats and endothelial cell migration.Methods:
ALT-C was purified by two steps of gel filtration followed by anion exchange chromatography. The α2ß1, integrin binding properties of ALT-C, its dissociation constant (Kd) relative to this integrin and to collagen I (Col I) were determined by surface plasmon resonance. The effects of ALT-C (10, 40, 100 and 1000 nM) in migration assays were studied using three human cell lines human fibroblasts, breast tumor cell line MDA-MB-231, and microvascular endothelial cells HMEC-1, considering cells found in the tumor microenvironment. ALT-C effects on MMP-9 and MMP-2 expression and activity were analyzed by quantitative PCR and gelatin zymography, respectively. Focal adhesion kinase activation was determined by western blotting.Results:
Our data demonstrate that ALT-C, after binding to α2ß1 integrin, acts by two distinct mechanisms against tumor progression, depending on the cell type in tumor cells, ALT-C decreases MMP-9 and MMP-2 contents and activity, but increases focal adhesion kinase phosphorylation and transmigration; and in endothelial cells, ALT-C inhibits MMP-2, which is necessary for tumor angiogenesis. ALT-C also upregulates c-Myc mRNA level, which is related to tumor suppression.Conclusion:
These results demonstrate that α2ß1 integrin controls MMP expression and reveal this integrin as a target for the development of antiangiogenic and antimetastatic therapies.(AU)
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Asunto principal:
Neoplasias de la Mama
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Metaloproteinasa 2 de la Matriz
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Metaloproteinasa 9 de la Matriz
/
Venenos de Crotálidos
/
Integrina alfa2beta1
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Células Endoteliales
Límite:
Animales
/
Humanos
Idioma:
Inglés
Revista:
J. venom. anim. toxins incl. trop. dis
Asunto de la revista:
Toxicología
Año:
2018
Tipo del documento:
Artículo
/
Documento de proyecto
País de afiliación:
Brasil
Institución/País de afiliación:
Federal University of São Carlos (UFSCar)/BR
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