Src kinase activation by nitric oxide promotes resistance to anoikis in tumour cell lines |
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Authors: | Paulo E. da Costa Wagner L. Batista Miriam S. Moraes Arnold Stern |
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Affiliation: | 1. Department of Biochemistry– Center for Cellular and Molecular Therapy (CTCMol), Escola Paulista de Medicina - Universidade Federal de S?o Paulo, Campus S?o Paulo, S?o Paulo, Brazil;2. Department of Pharmaceutical Sciences, Universidade Federal de S?o Paulo, Campus Diadema, S?o Paulo, Brazil;3. Institute of Biosciences, Universidade de S?o Paulo, S?o Paulo, Brazil;4. New York University School of Medicine, New York, NY, USA |
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Abstract: | Tumour progression involves the establishment of tumour metastases at distant sites. Resistance to anoikis, a form of cell death that occurs when cells lose contact with the extracellular matrix and with neighbouring cells, is essential for metastases. NO has been associated with anoikis. NO treated HeLa cells and murine melanoma cells in suspension triggered a nitric oxide (NO)-Src kinase signalling circuitry that enabled resistance to anoikis. Two NO donors, sodium nitroprusside (SNP) (500 µM) and DETANO (125 µM), protected against cell death derived from detachment of a growth permissive surface (experimental anoikis). Under conditions of NO-mediated Src activation the following were observed: (a) down-regulation of the pro-apoptotic proteins Bim and cleaved caspase-3 and the cell surface protein, E-cadherin, (b) up-regulation of caveolin-1, and (c) the dissociation of cell aggregates formed when cells are detached from a growth permissive surface. Efficiency of reattachment of tumour cells in suspension and treated with different concentrations of an NO donor, was dependent on the NO concentration. These findings indicate that NO-activated Src kinase triggers a signalling circuitry that provides resistance to anoikis, and allows for metastases. |
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Keywords: | Nitric oxide S-nitrosylation Src kinase Anoikis Anoikis resistance |
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