Endocrine Abstracts

Somatic mutations in splicing factor 3 subunit B1 (SF3B1) were found in about 20% of PRL-secreting PitNETs. SF3B1 is involved in pre-mRNA splicing and required for assembly of the U2 complex, which is critical for branch site recognition and the early stages of spliceosome assembly. Patients with mutant prolactinomas showed higher PRL levels and shorter progression-free survival compared to wild-type patients. Aims of the present study were: 1) to characterize the genetic prof...

Dopamine receptor type 2 (DRD2) agonists (DA) are the first-choice treatment for prolactin (PRL)-secreting pituitary tumors, but poorly effective in non-functioning (NF)-PitNETs. Along with G protein-dependent signaling, DRD2 also mediates non-canonical beta-arrestin-dependent pathways, where reduction of AKT phosphorylation plays a leading role for the antiproliferative effect of DRD2 in pituitary tumors. Through UNC9994 and MLS1547, a beta-arrestin 2-biased and a G protein-b...

Adrenocortical carcinomas (ACCs) are rare endocrine tumors with poor prognosis. They overexpress the insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR. The majority of studies focused on IGF1R as mediator of IGF2 biological effects, but recently a high expression of IR, in particular of the isoform A, was observed in most ACCs, suggesting a potential role of this receptor in modulating IGF2 effects in adrenocortical tumo...

Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favorable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mut...

The mTOR inhibitor everolimus has been shown to display antimitotic effects on diverse neoplasms, including pituitary neuroendocrine tumors (PitNETs); however, its effect is reduced by an escape mechanism that increases AKT phosphorylation (P-AKT) leading to survival pathway activation. Dopamine receptor type 2 (DRD2) reduces p-AKT in some non-functioning PitNETs (NF-PitNETs) and in lactotrophs MMQ cells, through a α-arrestin 2-dependent mechanism. This study aim...

The main target of pharmacological therapy for growth hormone (GH)-secreting pituitary tumors (GH-PitNET) is the somatostatin receptor type 2 (SST2). However, approximately half of patients treated with octreotide, an SST2 agonist, show a low response rate or are octreotide-resistant. Here we present mechanistic data that shows co-treatment with simufilam, a novel oral therapeutic candidate, enhances sensitivity to octreotide. We previously showed that the cytoskeleton protein...

The cytoskeletal actin-binding protein filamin A (FLNA) is poorly expressed in adrenocortical carcinomas (ACC) compared to adenomas (ACA), and this might contribute to sustain the increased cell proliferation by downregulating IGF1R expression and its downstream signaling. In mouse neural progenitor cells, increased protein expression levels of the CDK1 kinase Wee1 have been found after loss of FLNA. This protein has a leading role in regulating the G2-M checkpoint and functio...

Adrenocortical carcinomas (ACC) are rare endocrine tumors that originate in the cortex of the adrenal gland. They are characterized by the overexpression of insulin-like growth factor 2 (IGF2), whose bond with two tyrosine-kinase receptors, IGF1R and IR, activates a cancer-promoting signalling cascade. Another component of the IGF system is mannose 6-phosphate/insulin-like growth factor 2 receptor (IGF2R), a scavenger receptor able to bind specifically IGF2. Its main role is t...

The majority of adrenocortical carcinomas (ACC) overexpress insulin-like growth factor 2 (IGF2). Although IGF2 drives a proliferative autocrine loop by binding to IGF1R and the isoform A of the insulin receptor (IRA), most studies focused on IGF1R. Recently, a high expression of IRA was observed in ACC vs normal adrenal tissues (NA), suggesting its potential involvement in modulating IGF2 effects in adrenocortical tumorigenesis. Aim of this study was to investigate the specifi...

Dopamine receptor type 2 (DRD2) represents the main target for pharmacological therapy with dopamine agonists (DAs) in PRL-secreting neuroendocrine pituitary tumors (PRL-PitNET), even if about 10% of patients is resistant. A single paper recently described a somatic mutation in the gene encoding splicing factor 3B subunit 1 (SF3B1) in about 20% of patients with PRL-PitNET, that was associated with PRL hypersecretion, increased cell proliferation and invasion and reduced progre...