Dose terapêutica de radiação ionizante induz um fenótipo migratório em células de carcinoma de colon humano (caco-2): vias de sinalização envolvidas

Abstract

The colorectal cancer (CRC) is one of the most common tumours among population and the local recurrence and second malignancies still the main problem in the treatment of CRC. Radiotherapy (RT) is used as first line of treatment in combination with surgical process. To improve better results, multidisciplinary strategies that use RT, surgical process and chemotherapy have been used in clinical protocols. However, not all over the patients get the successfully therapeutic, and disease refractory has become occurred. Furthermore, beside the acute and later effects after RT, in special at gastrointestinal tract, are so important to improve quality of life for patients. These effects are correlated with alterations at intestinal epithelium homeostasis, with apical junctions (AJ) disassembly. The signaling pathways that mediate these alterations are not elucidated. The aim of this study was investigate the cell signaling pathways that guide the IR effect on AJ disassembly, cytoskeleton organization, the migratory potential and the cell proliferation in Caco-2 cells. Ours results showed that the disassembly of AJ by IR was mediate by Src, EGFR and MAPK. These effects were accompanied by cytoskeleton disorganization at all over cellular volume. Src, EGFR and MAPK are involved in this process in a differential manner. We also observed that IR induces a migratory potential in Caco-2 cells by Src and MAPK pathways and didn´t alters the cell proliferation at 48 hours. This is the first work that correlated cell signaling survival (Src, EGFR, and MAPK) and cell-cell contacts disassembly, actin cytoskeleton reorganization and cell migration, events that guide acute and later effects of IR. These events, in turn, induce a heritable malignant phenotype during radiotherapy fractionation and improve CRC tumour progression at later stages. In conclusion, the study of signaling pathways that guide these effects are important to understand the recurrence of disease after radiotherapy and a better understanding of pharmacological activity of these chemical inhibitors used here, once that some of them are used in pre-clinical studies.