Chemical modulation of VLA integrin affinity in human breast cancer cells.

Abstract

The fact that disruption of integrin-extracellular matrix contacts leads to cell death, has converted cell adhesion into a potential target for the control of invasive cancer. In this work, we studied the functional consequences of the interference with the activity of the very late activation antigen (VLA) family of integrins in human breast cancer cell lines of distinct malignancy. The alpha2beta1-mediated adhesion reduced the entry of highly malignant, hormone-independent breast cancer cells into apoptosis. Adhesion of breast cancer cells through the VLA integrins alpha2beta1 and alpha5beta1 was significantly reduced by an apoptosis-inducing natural triterpenoid, dehydrothyrsiferol (DT), when studied on low amounts of extracellular matrix. This effect was dose-dependent, not related to cell toxicity and not shared with apoptosis-inducing standard chemotherapeutics, such as doxorubicin and taxol. The compound did not affect either the cell surface expression level of VLA integrins or cell distribution of vinculin and actin during cell spreading. In addition, neither phosphorylation of the focal adhesion kinase pp125FAK on Tyr397 nor the protein kinase B (Akt/PKB) on Ser473 was significantly altered by DT. The integrin activation level, assessed by binding of soluble collagen to the alpha2beta1 integrin, was reduced upon cell treatment with DT. Importantly, the TS2/16, an anti-beta1 activating monoclonal antibody was able to rescue DT-treated cells from apoptosis. Since the activation state of integrins is increasingly recognized as an essential factor in metastasis formation, findings presented herein reveal that the chemical regulation of integrin affinity may be a potential therapeutic strategy in cancer therapy.

• Authors: Martina K Pec, Michaela Artwohl, José J Fernández, María L Souto, Diego Alvarez de la Rosa, Teresa Giraldez, Agustín Valenzuela-Fernández, Federico Díaz-González
• Journal: Experimental cell research (Exp Cell Res) Vol. 313 Issue 6 Pg. 1121-34 (Apr 01 2007) ISSN: 0014-4827 [Print] United States
• PMID: 17331499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Integrin alpha2beta1
• Integrin alpha5beta1
• Integrins
• Pyrans
• Receptors, Very Late Antigen
• dehydrothyrsiferol
• Vinculin
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Actins (metabolism)
• Apoptosis
• Breast Neoplasms (metabolism)
• Cell Adhesion
• Cell Line, Tumor
• Extracellular Matrix (metabolism, physiology)
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• Integrin alpha2beta1 (metabolism, physiology)
• Integrin alpha5beta1 (metabolism, physiology)
• Integrins (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrans (pharmacology)
• Receptors, Very Late Antigen (metabolism)
• Vinculin (metabolism)