INBIOSUR   25013
INSTITUTO DE CIENCIAS BIOLOGICAS Y BIOMEDICAS DEL SUR
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Modulation by PTHrP of molecular mechanisms associated with the induction of cancer stem cell phenotype and epithelial to mesenchymal transition in human colorectal cancer cells
Autor/es:
CALVO, NATALIA; CARRIERE, PEDRO; GENTILI, CLAUDIA; NOVOA DIAZ, BELEN; MARTÍN, MA. JULIA
Lugar:
Mar del Plata
Reunión:
Congreso; LXIII reunion Anual De la Sociedad Argentina de Investigación Clínica; 2018
Resumen:
Parathyroid hormone-related peptide (PTHrP) is expressed in many colorectal cancer (CRC) patients. This disease is the second most common cancer in Argentina. In Caco-2 and HCT116 cell lines, both derived from human CRC, we found that PTHrP exerts proliferative and protective effects, induces cell migration, and promotes tumor-associated angiogenesis. PTHrP also attenuates the sensitivity of these cells to the chemotherapeutic drug Irinotecan through ERK MAPK and β-catenin pathways. Herein we further investigated the mechanism modulated by PTHrP leading to a more aggressive phenotype of CRC cells employing HCT116 cells and HCT116 tumor xenografts in nude mice. In vitro we found that PTHrP induces Ser552 phosphorylation of β-catenin and its subsequent nuclear translocation. Once in the nucleus, β-catenin can activate the expression of molecular markers associated with other events of CRC progression such as cancer stem cell (CSC) phenotype and epithelial to mesenchymal transition (EMT). In both experimental models we observed that PTHrP regulates protein levels of two CSC markers, CD44 and CD24 and also modulates protein expression of the EMT markers, CK-18, E-cadherin and ZEB-1. Met is a receptor tyrosine kinase (RTK) with aberrant expression and signaling in advanced CRC. We found that PTHrP decreases Met protein levels being this effect reverted by ERK1/2 and p38 MAPK specific inhibitors, suggesting that in PTHrP-treated HCT116 cells this RTK is degraded after its activation via MAPK signaling. According with our hypothesis, PTHrP increases Met protein levels in the murine model. Finally, the specific Met inhibitor reverted β-catenin phosphorylation and EMT markers expression induced by PTHrP suggesting that Met signaling is involved in these molecular events. Advances in the knowledge of the characteristics of aggressive CRC, such as the induction of CSC or EMT, will provide valuable information in understanding this disease and will facilitate the development of new therapeutic approaches.