Endocrine Abstracts

Pituitary tumors, are mostly benign, but may cause significant morbidity in affected patients, including visual and neurologic manifestations from mass-effect, or endocrine syndromes caused by hormone hypersecretion. Dopamine (DA) receptor DRD2 and somatostatin (SS) receptors (SSTRs) represent the main targets of pharmacological treatment of pituitary tumors since they mediate inhibitory effects on both hormone secretion and cell proliferation, and their expression is retained by most of these tumors. Although long acting DA and SS analogs are currently used in the treatment of prolactin (PRL)- and growth hormone (GH)-secreting pituitary tumors, respectively, clinical practice indicates a great variability in the frequency and entity of favourable responses. The molecular basis of the pharmacological resistance as well as of clinical aggressiveness are still poorly understood, and several potential molecular mechanisms have been proposed, including defective expression or genetic alterations of DRD2 and SSTRs, or an impaired signal transduction. Recently, cytoskeleton has emerged as novel player implicated in the complex mechanisms of pharmacological resistance of pituitary tumors to DA and SS. In the past 5 years the speaker’s group demonstrated that specific cytoskeleton proteins play a key role both in determining tumor clinical aggressiveness and invasion, and in modulating responsiveness to currently used drugs, by regulating receptor localization/signaling. In particular, we demonstrated a role for cytoskeleton protein filamin A (FLNA) in DRD2 and SSTRs receptors expression and signalling in PRL- and GH- secreting tumors, respectively, first revealing a link between FLNA expression and responsiveness of pituitary tumors to pharmacological therapy. Moreover, another cytoskeleton actin binding protein, cofilin, was shown to be a determinant and potential new biomarker for pituitary tumor invasiveness. In this respect, we recently showed that invasiveness of pituitary tumors is promoted by the activation of cofilin, that can be in turn regulated by DRD2. Indeed, DRD2 agonist reduced migration/invasion and increased phosphorylated inactive cofilin in non-functioning pituitary tumoral cells. The talk will provide an overview of the known molecular events involved in SS and DA resistance, focusing on the role played by cytoskeleton by showing both published and unpublished observations.