PMID- 35721701
OWN - NLM
STAT- MEDLINE
DCOM- 20220621
LR  - 20220728
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 13
DP  - 2022
TI  - DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor 
      Everolimus in Tumoral Pituitary Cells.
PG  - 867822
LID - 10.3389/fendo.2022.867822 [doi]
LID - 867822
AB  - The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to 
      display antiproliferative effects on a wide spectrum of tumors. In vitro studies 
      demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) 
      cell growth in a subset of patients. Sensitivity to everolimus is reduced by an 
      escape mechanism that increases AKT phosphorylation (p-AKT), leading to 
      pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a 
      reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in 
      prolactin-secreting tumor cells (MMQ cells) through a beta-arrestin 2-dependent 
      mechanism. The aim of this study was to investigate the efficacy of everolimus 
      combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and 
      MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of 
      beta-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, 
      but the combined treatment with cabergoline inhibited cell proliferation in 7 out 
      of 9 tumors (-31.4 +/- 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. 
      In the everolimus-unresponsive NF-PitNET group, everolimus determined a 
      significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) 
      that was reverted by cabergoline cotreatment. To investigate the molecular 
      mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. 
      Indeed everolimus did not affect MMQ cell proliferation and increased the 
      p-AKT/total-AKT ratio (+1.53 +/- 0.24-fold, p < 0.001 vs. basal), whereas 
      cabergoline significantly reduced cell proliferation (-22.8 +/- 6.8%, p < 0.001 vs. 
      basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a 
      reduction of both cell proliferation (-34.8 +/- 18%, p < 0.001 vs. basal and p < 
      0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 +/- 14%, p < 0.001 vs. 
      basal and p < 0.05 vs. cabergoline alone). To test beta-arrestin 2 involvement, 
      silencing experiments were performed in MMQ cells. Our data showed that the lack 
      of beta-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory 
      effects on both p-AKT and cell proliferation. In conclusion, this study revealed 
      that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and 
      tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration 
      of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way 
      for a potential combined therapy in beta-arrestin 2-expressing NF-PitNETs or other 
      PitNETs resistant to conventional treatments.
CI  - Copyright (c) 2022 Mangili, Esposito, Treppiedi, Catalano, Marra, Di Muro, 
      Barbieri, Locatelli, Lania, Mangone, Spada, Arosio, Peverelli and Mantovani.
FAU - Mangili, Federica
AU  - Mangili F
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Esposito, Emanuela
AU  - Esposito E
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Treppiedi, Donatella
AU  - Treppiedi D
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Catalano, Rosa
AU  - Catalano R
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Marra, Giusy
AU  - Marra G
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Di Muro, Genesio
AU  - Di Muro G
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Barbieri, Anna Maria
AU  - Barbieri AM
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Locatelli, Marco
AU  - Locatelli M
AD  - Neurosurgery Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico 
      (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
AD  - Department of Pathophysiology and Transplantation, University of Milan, Milan, 
      Italy.
FAU - Lania, Andrea G
AU  - Lania AG
AD  - Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.
AD  - Endocrinology and Diabetology Unit, Istituto di Ricovero e Cura a Carattere 
      Scientifico (IRCCS) Humanitas Research Hospital, Rozzano, Italy.
FAU - Mangone, Alessandra
AU  - Mangone A
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
AD  - Endocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere 
      Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
FAU - Spada, Anna
AU  - Spada A
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Arosio, Maura
AU  - Arosio M
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
AD  - Endocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere 
      Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
FAU - Peverelli, Erika
AU  - Peverelli E
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
FAU - Mantovani, Giovanna
AU  - Mantovani G
AD  - Department of Clinical Sciences and Community Health, University of Milan, Milan, 
      Italy.
AD  - Endocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere 
      Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220603
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 0 (DRD2 protein, human)
RN  - 0 (Receptors, Dopamine D2)
RN  - 0 (beta-Arrestin 2)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - LL60K9J05T (Cabergoline)
SB  - IM
MH  - *Cabergoline/pharmacology
MH  - Drug Interactions
MH  - *Everolimus/pharmacology
MH  - Humans
MH  - *Neuroendocrine Tumors/drug therapy/metabolism/pathology
MH  - *Pituitary Neoplasms/drug therapy/metabolism/pathology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - *Receptors, Dopamine D2/agonists/metabolism
MH  - *TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - beta-Arrestin 2/metabolism
PMC - PMC9204243
OTO - NOTNLM
OT  - AKT phosphorylation
OT  - cabergoline
OT  - dopamine receptor type 2
OT  - everolimus
OT  - mTOR inhibitors
OT  - pituitary neuroendocrine tumors
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/06/21 06:00
MHDA- 2022/06/22 06:00
PMCR- 2022/01/01
CRDT- 2022/06/20 03:58
PHST- 2022/02/01 00:00 [received]
PHST- 2022/04/04 00:00 [accepted]
PHST- 2022/06/20 03:58 [entrez]
PHST- 2022/06/21 06:00 [pubmed]
PHST- 2022/06/22 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2022.867822 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2022 Jun 3;13:867822. doi: 
      10.3389/fendo.2022.867822. eCollection 2022.