ECE2022 Oral Communications Oral Communications 7: Pituitary and Neuroendocrinology 2 (6 abstracts)
Splicing factor 3 subunit B1 (SF3B1) inhibition in PRL-secreting PitNETs and cross-talk with dopamine receptor type 2 (DRD2)
Genesio Di Muro 1,2 , Federica Mangili 2 , Anna Maria Barbieri 2 , Emanuela Esposito 2 , Donatella Treppiedi 2 , Federico Arlati 2 , Rosa Catalano 2 , Giusy Marra 2 , Emma Nozza 2 , Maura Arosio 2,3 , Giovanna Mantovani 2,3 & Erika Peverelli 2
1University Sapienza of Rome, PhD Program in Endocrinological Sciences, Italy; 2University of Milan, Department of Clinical Sciences and Community Health, Italy; 3Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Italy
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 profile of a cohort of 14 patients with PRL-secreting PitNETs, searching for somatic mutations in SF3B1 hotspot region; 2) to test the effects of SF3B1 inhibitor pladienolide-B on tumoral lactotroph cells; 3) to investigate dopamine receptor type 2 (DRD2) agonist effects in tumoral lactotroph cells silenced for SF3B1. We found no SF3B1 mutated patients in our cohort. In rat PRL-secreting pituitary tumoral cells MMQ, pladienolide-B was effective in reducing cell proliferation (-40 ± 10% at 20 nM, P<0.001 vs basal), viability (-42 ± 7% at 10 nM, P<0.05 vs basal) and in promoting apoptosis (6-fold increase at 50 nM, P< 0.05 vs basal). In primary cultured cells from one PRL-secreting PitNET, bearing wild-type SF3B1, pladienolide-B reduced cell proliferation and cyclin D3 expression and increased cell apoptosis. SF3B1 silencing in MMQ cells induced a reduction of DRD2 expression (-51 ± 13.2%, P<0.001 vs control cells). Moreover, in MMQ cells lacking SF3B1, cabergoline completely lost its ability to reduce cell proliferation (-22 ± 4.8%, P< 0.001 vs basal), AKT phosphorylation (-31 ± 24,6%, P<0.01 vs basal), cyclin D3 expression (-23 ± 7,6%, P<0.05 vs basal) and to increase p27 (+20 ± 8,6%, P<0.05 vs basal). Interestingly, cabergoline treatment reduced SF3B1 protein expression levels in MMQ cells (-60 ± 40%, P<0.05 vs control cells) and in primary cultured cells from 2 PRL-secreting PitNETs (-43 ± 6,4%, P<0.01). In conclusion, our data demonstrated that SF3B1 inhibitor pladienolide-B exerts antitumoral actions in PRL-secreting PitNET cells bearing wild-type SF3B1. In MMQ cells, SF3B1 silencing reduced DRD2 expression and signaling, and cabergoline negatively regulated SF3B1 expression.
Volume 81
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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