| Full text | |
| Author(s): |
de Oliveira Moritz, Milene Nobrega
[1]
;
Santos Eustaquio, Livia Mara
[1]
;
Micocci, Kelli Cristina
[1]
;
Caetano Nunes, Ana Carolina
[1]
;
dos Santos, Patty Karina
[1]
;
Vieira, Tamires de Castro
[1]
;
Selistre-de-Araujo, Heloisa Sobreiro
[1]
Total Authors: 7
|
| Affiliation: | [1] Fed Univ Sao Carlos UFSCar, Dept Physiol Sci, BR-13565905 Sao Carlos, SP - Brazil
Total Affiliations: 1
|
| Document type: | Journal article |
| Source: | Journal of Venomous Animals and Toxins including Tropical Diseases; v. 24, APR 25 2018. |
| Web of Science Citations: | 4 |
| 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 a2 beta 1 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 a2 beta 1 integrin. Herein, we used ALT-C as a a2 beta 1 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 a2 beta 1 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 a2 beta 1 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 a2 beta 1 integrin controls MMP expression and reveal this integrin as a target for the development of antiangiogenic and antimetastatic therapies. (AU) | |
| FAPESP's process: | 14/17651-7 - The alfa2beta1 integrin in breast tumor progression: the role in tumor microenvironment and metastasis |
| Grantee: | Milene Nóbrega de Oliveira Moritz |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 13/00798-2 - The extracellular matrix in aging, exercise and in the tumor microenvironment |
| Grantee: | Heloisa Sobreiro Selistre de Araújo |
| Support Opportunities: | Research Projects - Thematic Grants |