IL RECETTORE DELLA DOPAMINA DI TIPO 2 (DRD2) INIBISCE LA MIGRAZIONE DI CELLULE DI ADENOMA IPOFISARIO NON SECERNENTE TRAMITE INATTIVAZIONE DI COFILINA

Non-functioning pituitary adenomas (NFPAs) are benign in nature, frequently present local invasiveness that strongly reduces neurosurgery success. Medical therapy is still under debate, although evidences indicate that dopamine (DA) receptor 2 (DRD2) agonists induce tumor shrinkage in some patients. Aims of this study were: to evaluate the effect of DR2D agonist BIM53097 on migration and invasion of NFPA cells, and to investigate the molecular mechanisms regulating the motility of these cells, focusing on the role of cofilin, an actin severing protein involved in actin reorganization. Our data demonstrated that BIM53097 incubation significantly reduced cell migration (42±6% p<0.05) and invasion (32±2%, p<0.01) and increased about 4-fold cofilin phosphorylation at Ser3 in a subset of NFPAs, these data being replicated in HP75 cells. Both these effects were completely abolished by ROCK inhibitor Y-27632. The overexpression of wild type or phospho-deficient (S3A) cofilin in HP75 cells increased cell migration (49±6% and 57±9% increase vs empty vector, respectively, p<0.05), suggesting a causal role for active (dephosphorylated) cofilin in cell motility. In agreement, invasive NFPAs showed lower phospho-cofilin/total cofilin ratio with respect to non invasive tumors. In conclusion, our data reveal that DRD2 agonist reduced NFPA cells migration through a molecular mechanism that involves ROCK-dependent phosphorylation of cofilin, and suggest that cofilin phosphorylation status might be a molecular marker associated with the invasive behaviour of NFPAs.