{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T03:35:50Z","timestamp":1773113750032,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T00:00:00Z","timestamp":1583107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.<\/jats:p>","DOI":"10.3390\/ijms21051700","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T07:50:53Z","timestamp":1583135453000},"page":"1700","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition"],"prefix":"10.3390","volume":"21","author":[{"given":"Ilaria","family":"Cristofaro","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnologies Charles Darwin, Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Limongi","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies Charles Darwin, Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Piscopo","sequence":"additional","affiliation":[{"name":"Depatment of Neuroscience, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Crestini","sequence":"additional","affiliation":[{"name":"Depatment of Neuroscience, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Guerriero","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies Charles Darwin, Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Fiore","sequence":"additional","affiliation":[{"name":"IBPM, Institute of Molecular Biology and Pathology, CNR, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2050-9846","authenticated-orcid":false,"given":"Luciano","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology\u2014CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-8536","authenticated-orcid":false,"given":"Annamaria","family":"Confaloni","sequence":"additional","affiliation":[{"name":"Depatment of Neuroscience, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4868-5435","authenticated-orcid":false,"given":"Ada Maria","family":"Tata","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies Charles Darwin, Sapienza, University of Rome, 00185 Rome, Italy"},{"name":"Research center of Neuroscience, Sapienza, University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/jnen\/61.3.215","article-title":"The WHO classification of tumors of the nervous system","volume":"61","author":"Kleihues","year":"2002","journal-title":"J. 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