Endocrine Abstracts

Non-functioning pituitary tumors (NFPTs), although benign in nature, frequently present local invasiveness that strongly reduces neurosurgery success. Medical therapy is still under debate, although dopamine (DA) receptor 2 (DRD2) agonists may induce tumor shrinkage in some patients. Aims of this study were: 1) to evaluate the effect of DR2D agonist BIM53097 on migration and invasion of NFPT cells, 2) to investigate the molecular mechanisms regulating the motility of these cells, focusing on the role of cofilin, an actin severing protein involved in actin remodelling required for migration, 3) to test cofilin expression and its phosphorylation levels in NFPT tissues characterized or not by invasion of the cavernous sinus.

Our data demonstrated that BIM53097 significantly reduced migration (-42±6% P<0.05) and invasion (-32±2%, P<0.01) and increased about 4-fold cofilin phosphorylation at Ser3 in cultured cells derived from human surgically removed NFPTs, these data being replicated in HP75 cell line. Both these effects were completely abolished by an inhibitor of ROCK, a Rho-associated kinase involved in cofilin phosphorylation. The overexpression of wild type or phospho-deficient (S3A) cofilin in HP75 cells increased cell migration (+49±6% and +57±9% vs empty vector, respectively, P<0.05), suggesting a causal role for active (dephosphorylated) cofilin in cell motility.

Interestingly, we observed that most invasive tumors showed nearly absent P-cofilin, in contrast to high levels of P-cofilin showed by most non-invasive tumors by both immunohistochemistry and western blot analysis (0.008 and 0.524 median P-cofilin/tot-cofilin ratio, respectively, P<0.05).

In conclusion, our data demonstrated that DRD2 agonist reduces NFPT cells migration and invasion through a molecular mechanism that involves ROCK-dependent phosphorylation of cofilin. Moreover, NFPT invasion of the cavernous sinus associates with increased active (dephosphorylated) cofilin, suggesting that cofilin phosphorylation status might be a novel molecular marker of the invasive behaviour of NFPTs.