The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway
| Autor: | Hayder Dyer, Tracy Robson, Christopher T. Elliott, Hayley D. McKeen, Lynn McCallum, Anita Yakkundi, Anthony A O'Kane, Lana McClements, Jenny Worthington, David G. Hirst, Helen O. McCarthy |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
RHOA
Non-Clinical Medicine Angiogenesis Cancer Treatment Invasive Ductal Carcinoma lcsh:Medicine Metastasis 0302 clinical medicine Tubulin Cell Movement Molecular Cell Biology Basic Cancer Research Breast Tumors lcsh:Science Cytoskeleton Medicine(all) rho-Associated Kinases 0303 health sciences Multidisciplinary biology Agricultural and Biological Sciences(all) Cell migration Vinculin Cellular Structures Antigens CD44 Extracellular Matrix Cell biology Ductal Carcinoma in Situ Hyaluronan Receptors Oncology Profilin Gene Knockdown Techniques 030220 oncology & carcinogenesis Medicine Antiangiogenesis Therapy Research Article Signal Transduction General Science & Technology Molecular Sequence Data Academic Medicine Cell Growth Cell Line Tacrolimus Binding Proteins 03 medical and health sciences FKBPL Cell Adhesion Humans Amino Acid Sequence Actin-binding protein Immunophilins Biology 030304 developmental biology Biochemistry Genetics and Molecular Biology(all) lcsh:R Cancers and Neoplasms Actin cytoskeleton Actins Gene Expression Regulation biology.protein lcsh:Q Peptides |
| Zdroj: | Yakkundi, A, McCallum, L, O'Kane, A, Dyer, H, Worthington, J, McKeen, H D, McClements, L, Elliott, C, McCarthy, H O, Hirst, D G & Robson, T 2013, ' The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway ', PLoS ONE, vol. 8, no. 2, e55075 . https://doi.org/10.1371/journal.pone.0055075 PLoS ONE, Vol 8, Iss 2, p e55075 (2013) PLoS ONE |
| Popis: | FK506 binding protein-like (FKBPL) and its peptide derivatives exert potent anti-angiogenic activity in vitro and in vivo and control tumour growth in xenograft models, when administered exogenously. However, the role of endogenous FKBPL in angiogenesis is not well characterised. Here we investigated the molecular effects of the endogenous protein and its peptide derivative, AD-01, leading to their anti-migratory activity. Inhibition of secreted FKBPL using a blocking antibody or siRNA-mediated knockdown of FKBPL accelerated the migration of human microvascular endothelial cells (HMEC-1). Furthermore, MDA-MB-231 tumour cells stably overexpressing FKBPL inhibited tumour vascular development in vivo suggesting that FKBPL secreted from tumour cells could inhibit angiogenesis. Whilst FKBPL and AD-01 target CD44, the nature of this interaction is not known and here we have further interrogated this aspect. We have demonstrated that FKBPL and AD-01 bind to the CD44 receptor and inhibit tumour cell migration in a CD44 dependant manner; CD44 knockdown abrogated AD-01 binding as well as its anti-migratory activity. Interestingly, FKBPL overexpression and knockdown or treatment with AD-01, regulated CD44 expression, suggesting a co-regulatory pathway for these two proteins. Downstream of CD44, alterations in the actin cytoskeleton, indicated by intense cortical actin staining and a lack of cell spreading and communication were observed following treatment with AD-01, explaining the anti-migratory phenotype. Concomitantly, AD-01 inhibited Rac-1 activity, up-regulated RhoA and the actin binding proteins, profilin and vinculin. Thus the anti-angiogenic protein, FKBPL, and AD-01, offer a promising and alternative approach for targeting both CD44 positive tumours and vasculature networks. © 2013 Yakkundi et al. |
| Databáze: | OpenAIRE |
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