Endocrine Abstracts

Somatostatin exerts inhibitory effects on hormone secretion and cell proliferation by interacting with five different receptors (SST1–SST5) linked to effector systems via G proteins. The receptor structural domains mediating these effects have not been identified. Since SS is the hypothalamic peptide that physiologically inhibits GH secretion, aim of this study was to investigate the molecular determinants mediating the interaction of the human SST5 with G proteins and su...

Despite the increasing evidence on the relevance of the actin binding protein filamin A (FLNA) in determining an efficient intracellular response to somatostatin analogs (SSA) in pituitary tumors, there is a gap in the knowledge on the mechanisms regulating FLNA itself. FLNA is phosphorylated by PKA on Ser2152 located in a FLNA region crucial for SST2 or partner proteins binding. Although cAMP/PKA pathway plays a crucial role in GH-secreting tumors pathogenesis, the...

Currently, the multi-ligand somatostatin (SS) analogue pasireotide (SOM230) is the only pituitary-targeted drug used to treat patients with Cushing’s disease. SOM230 displays the highest affinity to somatostatin receptor type 5 (SSTR5) and compared to octreotide resulted more effective in reducing ACTH release. Despite its anti-secretory role, SOM230 has been associated with tumor shrinkage in patients subjected to long term treatment, although to date the key factors inv...

Adrenocortical carcinomas (ACCs) are rare endocrine tumors with poor prognosis. The insulin-like growth factor 2 (IGF2) is overexpressed in the great majority of ACC, and IGF2/IGF1R pathway acts as a proliferative autocrine loop, but to date IGF1R-targeted therapies have demonstrated a limited efficacy and the molecular mechanisms regulating this pathway are still unknown. The cytoskeleton acting-binding protein filamin A (FLNA), determinant in cancer progression and metastasi...

Cushing’s Disease (CD) is a rare condition characterized by an overproduction of ACTH by an ACTH-secreting pituitary tumor, resulting in excess of cortisol release by the adrenal glands. Pasireotide is the pituitary-targeted drug approved to treat adult patients. Its mechanism of action seems to rely on the preferential binding to the highly expressed somatostatin receptor in corticotroph tumors, SST5. Recently, somatic mutations in the deubiquitinase USP8 gene h...

The high expression of somatostatin receptor 2 (SST2) in growth hormone (GH)-secreting tumors represents the rationale for the clinical use of somatostatin analogs (SSAs) in acromegaly. However, about one third of patients displays resistance to SSAs and, to date, the responsible molecular mechanisms are still under investigation. Recently, the cytoskeletal protein Filamin A (FLNA) and the scaffolding proteins β-arrestins have emerged as key modulators of the responsivene...

Cushing’s disease (CD) is a rare disorder of chronic hypercortisolism due to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. Pasireotide, a multireceptor-targeted somatostatin (SST) analog with high binding affinity for the predominant SST receptor in human corticotroph tumors, SST5, has been recently approved to treat adult patients for whom surgery failed or does not represent a suitable option. However, to date, the molecular predictors of antisecretor...

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that originates from parafollicular thyroid C cells and accounts for 5% -10% of thyroid cancers. In all inherited cases of MTC, and in about 40% of sporadic cases, activating mutations of the receptor tyrosine kinase proto-oncogene RET are found. Constitutively active RET triggers signaling pathways involved in cell proliferation, survival and motility, but the mechanisms underlying malignant transformation of C-...

Although generally benign, pituitary tumors frequently present local invasiveness that strongly reduces neurosurgery success. We recently demonstrated a role for the actin binding protein cofilin in promoting non functioning pituitary tumors invasiveness and an inhibitory effect of dopamine receptor type 2. Somatostatin (SS) receptor type 2 (SSTR2) is the main target of pharmacological therapy of GH-secreting pituitary tumors, reducing both GH secretion and cell proliferation,...

Pulmonary neuroendocrine tumors (PNTs) comprise a spectrum of neoplasms, ranging from low grade carcinoids to the highly malignant small cell lung cancers. Several studies identified cytoskeleton protein Filamin A (FLNA) as determinant in cancer progression and metastasis. To date, the role of FLNA in PNTs aggressiveness and progression is still unknown.To address this question, we decided: i) to evaluate FLNA expression in PNTs ranging from typical carc...