Loading…

A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells

The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2's antimitotic...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2023-06, Vol.15 (12), p.3218
Main Authors: Di Muro, Genesio, Mangili, Federica, Esposito, Emanuela, Barbieri, Anna Maria, Catalano, Rosa, Treppiedi, Donatella, Marra, Giusy, Nozza, Emma, Lania, Andrea G A, Ferrante, Emanuele, Locatelli, Marco, Arosio, Maura, Peverelli, Erika, Mantovani, Giovanna
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites cdi_FETCH-LOGICAL-c443t-2333a6b3ce36273528f6d4eba832b5e3f9927ab31f2ff0e10795525e50ca62f53
container_end_page
container_issue 12
container_start_page 3218
container_title Cancers
container_volume 15
creator Di Muro, Genesio
Mangili, Federica
Esposito, Emanuela
Barbieri, Anna Maria
Catalano, Rosa
Treppiedi, Donatella
Marra, Giusy
Nozza, Emma
Lania, Andrea G A
Ferrante, Emanuele
Locatelli, Marco
Arosio, Maura
Peverelli, Erika
Mantovani, Giovanna
description The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2's antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (-40.2 ± 20.4% vs. -21 ± 10.9%, < 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline's antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures ( = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.
doi_str_mv 10.3390/cancers15123218
format article
fullrecord <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10296728</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A754975944</galeid><sourcerecordid>A754975944</sourcerecordid><originalsourceid>FETCH-LOGICAL-c443t-2333a6b3ce36273528f6d4eba832b5e3f9927ab31f2ff0e10795525e50ca62f53</originalsourceid><addsrcrecordid>eNptksFu1DAQhiMEolXpmRuyxKUc0jp2HCcntOy2UGkpq2U5W453vHWV2MF2kPpaPAPnPlMdtZS2wj7Y8v_N75nRZNnbAh9T2uATJa0CHwpWEEqK-kW2TzAneVU15ctH973sMIQrnBalBa_462yPcspxTZr97M8M3fzOZ95DiMYikn8yMsAWLdwge2MBrUHBEJ1Hm-sBEEFHi_WCfECznbMmRHQe0FfnAZ1qbZRUxo0BbS6lRXPZgt-5bvJIxmvYjsrYHZpD16GVT4IGL6NxdpJX62X-HZSHODHtGNGFi5Nw4Wx-Nlo1gZO0MnE0UfprtBn7lNVkF95kr7TsAhzenwfZj7PTzfxLvvz2-Xw-W-aqLGnMCaVUVi1VQCvCKSO1rrYltLKmpGVAddMQLltaaKI1hgLzhjHCgGElK6IZPcg-3vkOY9vDVoGNXnZi8KZPGQknjXiqWHMpdu6XKDBpKk7q5HB07-DdzzH1XPQmqFSDtJBaJxKCq4pxXCb0_TP0yo3epvoSRRpe17is_1E72YEwVrv0sZpMxYyzsuGsKSev4_9QaW-hN8pZ0Ca9Pwk4uQtQ3oXgQT8UWWAxDZ94Nnwp4t3j3jzwf0eN3gKsrdZs</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2829788048</pqid></control><display><type>article</type><title>A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells</title><source>PubMed (Medline)</source><source>ProQuest - Publicly Available Content Database</source><creator>Di Muro, Genesio ; Mangili, Federica ; Esposito, Emanuela ; Barbieri, Anna Maria ; Catalano, Rosa ; Treppiedi, Donatella ; Marra, Giusy ; Nozza, Emma ; Lania, Andrea G A ; Ferrante, Emanuele ; Locatelli, Marco ; Arosio, Maura ; Peverelli, Erika ; Mantovani, Giovanna</creator><creatorcontrib>Di Muro, Genesio ; Mangili, Federica ; Esposito, Emanuela ; Barbieri, Anna Maria ; Catalano, Rosa ; Treppiedi, Donatella ; Marra, Giusy ; Nozza, Emma ; Lania, Andrea G A ; Ferrante, Emanuele ; Locatelli, Marco ; Arosio, Maura ; Peverelli, Erika ; Mantovani, Giovanna</creatorcontrib><description>The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2's antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (-40.2 ± 20.4% vs. -21 ± 10.9%, &lt; 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline's antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures ( = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers15123218</identifier><identifier>PMID: 37370829</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Agonists ; Antibiotics ; Arrestin ; Biological products industry ; Brain tumors ; Cabergoline ; Cell culture ; Cell growth ; Cell proliferation ; Comparative analysis ; Dopamine ; Dopamine D2 receptors ; Dopamine receptors ; G proteins ; Kinases ; Ligands ; Neuroendocrine tumors ; Pertussis ; Pertussis toxin ; Phenols ; Pituitary ; Pituitary hormones ; Proteins ; Signal transduction ; Software ; Tumor cell lines ; Tumor cells ; Tumors ; Whooping cough</subject><ispartof>Cancers, 2023-06, Vol.15 (12), p.3218</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 by the authors. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c443t-2333a6b3ce36273528f6d4eba832b5e3f9927ab31f2ff0e10795525e50ca62f53</cites><orcidid>0000-0003-4909-7512 ; 0000-0002-4424-7895 ; 0000-0002-2758-5841 ; 0000-0002-9065-3886 ; 0000-0002-0556-7650 ; 0000-0003-3988-3616</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2829788048/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2829788048?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37370829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Muro, Genesio</creatorcontrib><creatorcontrib>Mangili, Federica</creatorcontrib><creatorcontrib>Esposito, Emanuela</creatorcontrib><creatorcontrib>Barbieri, Anna Maria</creatorcontrib><creatorcontrib>Catalano, Rosa</creatorcontrib><creatorcontrib>Treppiedi, Donatella</creatorcontrib><creatorcontrib>Marra, Giusy</creatorcontrib><creatorcontrib>Nozza, Emma</creatorcontrib><creatorcontrib>Lania, Andrea G A</creatorcontrib><creatorcontrib>Ferrante, Emanuele</creatorcontrib><creatorcontrib>Locatelli, Marco</creatorcontrib><creatorcontrib>Arosio, Maura</creatorcontrib><creatorcontrib>Peverelli, Erika</creatorcontrib><creatorcontrib>Mantovani, Giovanna</creatorcontrib><title>A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2's antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (-40.2 ± 20.4% vs. -21 ± 10.9%, &lt; 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline's antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures ( = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.</description><subject>Agonists</subject><subject>Antibiotics</subject><subject>Arrestin</subject><subject>Biological products industry</subject><subject>Brain tumors</subject><subject>Cabergoline</subject><subject>Cell culture</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Comparative analysis</subject><subject>Dopamine</subject><subject>Dopamine D2 receptors</subject><subject>Dopamine receptors</subject><subject>G proteins</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Neuroendocrine tumors</subject><subject>Pertussis</subject><subject>Pertussis toxin</subject><subject>Phenols</subject><subject>Pituitary</subject><subject>Pituitary hormones</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Software</subject><subject>Tumor cell lines</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Whooping cough</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNptksFu1DAQhiMEolXpmRuyxKUc0jp2HCcntOy2UGkpq2U5W453vHWV2MF2kPpaPAPnPlMdtZS2wj7Y8v_N75nRZNnbAh9T2uATJa0CHwpWEEqK-kW2TzAneVU15ctH973sMIQrnBalBa_462yPcspxTZr97M8M3fzOZ95DiMYikn8yMsAWLdwge2MBrUHBEJ1Hm-sBEEFHi_WCfECznbMmRHQe0FfnAZ1qbZRUxo0BbS6lRXPZgt-5bvJIxmvYjsrYHZpD16GVT4IGL6NxdpJX62X-HZSHODHtGNGFi5Nw4Wx-Nlo1gZO0MnE0UfprtBn7lNVkF95kr7TsAhzenwfZj7PTzfxLvvz2-Xw-W-aqLGnMCaVUVi1VQCvCKSO1rrYltLKmpGVAddMQLltaaKI1hgLzhjHCgGElK6IZPcg-3vkOY9vDVoGNXnZi8KZPGQknjXiqWHMpdu6XKDBpKk7q5HB07-DdzzH1XPQmqFSDtJBaJxKCq4pxXCb0_TP0yo3epvoSRRpe17is_1E72YEwVrv0sZpMxYyzsuGsKSev4_9QaW-hN8pZ0Ca9Pwk4uQtQ3oXgQT8UWWAxDZ94Nnwp4t3j3jzwf0eN3gKsrdZs</recordid><startdate>20230616</startdate><enddate>20230616</enddate><creator>Di Muro, Genesio</creator><creator>Mangili, Federica</creator><creator>Esposito, Emanuela</creator><creator>Barbieri, Anna Maria</creator><creator>Catalano, Rosa</creator><creator>Treppiedi, Donatella</creator><creator>Marra, Giusy</creator><creator>Nozza, Emma</creator><creator>Lania, Andrea G A</creator><creator>Ferrante, Emanuele</creator><creator>Locatelli, Marco</creator><creator>Arosio, Maura</creator><creator>Peverelli, Erika</creator><creator>Mantovani, Giovanna</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4909-7512</orcidid><orcidid>https://orcid.org/0000-0002-4424-7895</orcidid><orcidid>https://orcid.org/0000-0002-2758-5841</orcidid><orcidid>https://orcid.org/0000-0002-9065-3886</orcidid><orcidid>https://orcid.org/0000-0002-0556-7650</orcidid><orcidid>https://orcid.org/0000-0003-3988-3616</orcidid></search><sort><creationdate>20230616</creationdate><title>A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells</title><author>Di Muro, Genesio ; Mangili, Federica ; Esposito, Emanuela ; Barbieri, Anna Maria ; Catalano, Rosa ; Treppiedi, Donatella ; Marra, Giusy ; Nozza, Emma ; Lania, Andrea G A ; Ferrante, Emanuele ; Locatelli, Marco ; Arosio, Maura ; Peverelli, Erika ; Mantovani, Giovanna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-2333a6b3ce36273528f6d4eba832b5e3f9927ab31f2ff0e10795525e50ca62f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Agonists</topic><topic>Antibiotics</topic><topic>Arrestin</topic><topic>Biological products industry</topic><topic>Brain tumors</topic><topic>Cabergoline</topic><topic>Cell culture</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Comparative analysis</topic><topic>Dopamine</topic><topic>Dopamine D2 receptors</topic><topic>Dopamine receptors</topic><topic>G proteins</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Neuroendocrine tumors</topic><topic>Pertussis</topic><topic>Pertussis toxin</topic><topic>Phenols</topic><topic>Pituitary</topic><topic>Pituitary hormones</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Software</topic><topic>Tumor cell lines</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>Whooping cough</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Muro, Genesio</creatorcontrib><creatorcontrib>Mangili, Federica</creatorcontrib><creatorcontrib>Esposito, Emanuela</creatorcontrib><creatorcontrib>Barbieri, Anna Maria</creatorcontrib><creatorcontrib>Catalano, Rosa</creatorcontrib><creatorcontrib>Treppiedi, Donatella</creatorcontrib><creatorcontrib>Marra, Giusy</creatorcontrib><creatorcontrib>Nozza, Emma</creatorcontrib><creatorcontrib>Lania, Andrea G A</creatorcontrib><creatorcontrib>Ferrante, Emanuele</creatorcontrib><creatorcontrib>Locatelli, Marco</creatorcontrib><creatorcontrib>Arosio, Maura</creatorcontrib><creatorcontrib>Peverelli, Erika</creatorcontrib><creatorcontrib>Mantovani, Giovanna</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>ProQuest research library</collection><collection>ProQuest Biological Science Journals</collection><collection>Research Library (Corporate)</collection><collection>ProQuest - Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Muro, Genesio</au><au>Mangili, Federica</au><au>Esposito, Emanuela</au><au>Barbieri, Anna Maria</au><au>Catalano, Rosa</au><au>Treppiedi, Donatella</au><au>Marra, Giusy</au><au>Nozza, Emma</au><au>Lania, Andrea G A</au><au>Ferrante, Emanuele</au><au>Locatelli, Marco</au><au>Arosio, Maura</au><au>Peverelli, Erika</au><au>Mantovani, Giovanna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells</atitle><jtitle>Cancers</jtitle><addtitle>Cancers (Basel)</addtitle><date>2023-06-16</date><risdate>2023</risdate><volume>15</volume><issue>12</issue><spage>3218</spage><pages>3218-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2's antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (-40.2 ± 20.4% vs. -21 ± 10.9%, &lt; 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline's antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures ( = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>37370829</pmid><doi>10.3390/cancers15123218</doi><orcidid>https://orcid.org/0000-0003-4909-7512</orcidid><orcidid>https://orcid.org/0000-0002-4424-7895</orcidid><orcidid>https://orcid.org/0000-0002-2758-5841</orcidid><orcidid>https://orcid.org/0000-0002-9065-3886</orcidid><orcidid>https://orcid.org/0000-0002-0556-7650</orcidid><orcidid>https://orcid.org/0000-0003-3988-3616</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2072-6694
ispartof Cancers, 2023-06, Vol.15 (12), p.3218
issn 2072-6694
2072-6694
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10296728
source PubMed (Medline); ProQuest - Publicly Available Content Database
subjects Agonists
Antibiotics
Arrestin
Biological products industry
Brain tumors
Cabergoline
Cell culture
Cell growth
Cell proliferation
Comparative analysis
Dopamine
Dopamine D2 receptors
Dopamine receptors
G proteins
Kinases
Ligands
Neuroendocrine tumors
Pertussis
Pertussis toxin
Phenols
Pituitary
Pituitary hormones
Proteins
Signal transduction
Software
Tumor cell lines
Tumor cells
Tumors
Whooping cough
title A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T14%3A27%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20%CE%B2-Arrestin%202-Biased%20Dopamine%20Receptor%20Type%202%20(DRD2)%20Agonist%20Is%20More%20Efficacious%20Than%20Cabergoline%20in%20Reducing%20Cell%20Proliferation%20in%20PRL-Secreting%20but%20Not%20in%20Non-Functioning%20Pituitary%20Tumor%20Cells&rft.jtitle=Cancers&rft.au=Di%20Muro,%20Genesio&rft.date=2023-06-16&rft.volume=15&rft.issue=12&rft.spage=3218&rft.pages=3218-&rft.issn=2072-6694&rft.eissn=2072-6694&rft_id=info:doi/10.3390/cancers15123218&rft_dat=%3Cgale_pubme%3EA754975944%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c443t-2333a6b3ce36273528f6d4eba832b5e3f9927ab31f2ff0e10795525e50ca62f53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2829788048&rft_id=info:pmid/37370829&rft_galeid=A754975944&rfr_iscdi=true