{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:55:40Z","timestamp":1790873740340,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondi Bando Ricerca FFO 2021","award":["822\/2021"],"award-info":[{"award-number":["822\/2021"]}]},{"name":"Progetti di Ateneo per la ricerca di base e avvio alla ricerca 2021-2022","award":["786\/2021"],"award-info":[{"award-number":["786\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>TMZ-resistance remains a main limitation in glioblastoma (GBM) treatment. TMZ is an alkylating agent whose cytotoxicity is modulated by O6-methylguanine-DNA methyltransferase (MGMT), whose expression is determined by MGMT gene promoter methylation status. The inflammatory marker COX-2 has been implicated in GBM tumorigenesis, progression, and stemness. COX-2 inhibitors are considered a GBM add-on treatment due to their ability to increase TMZ-sensitivity. We investigated the effect of TMZ on COX-2 expression in GBM cell lines showing different COX-2 levels and TMZ sensitivity (T98G and U251MG). \u03b2-catenin, MGMT, and SOX-2 expression was analyzed. The effects of NS398, COX-2 inhibitor, alone or TMZ-combined, were studied evaluating cell proliferation by the IncuCyte\u00ae system, cell cycle\/apoptosis, and clonogenic potential. COX-2, \u03b2-catenin, MGMT, and SOX-2 expression was evaluated by RT-PCR, Western blotting, and immunofluorescence and PGE2 by ELISA. Our findings, sustaining the role of COX-2\/PGE2 system in TMZ-resistance of GBM, show, for the first time, a relevant, dose-dependent up-regulation of COX-2 expression and activity in TMZ-treated T98G that, in turn, correlated with chemoresistance. Similarly, all the COX-2-dependent signaling pathways involved in TMZ-resistance also resulted in being up-modulated after treatment with TMZ. NS398+TMZ was able to reduce cell proliferation and induce cell cycle arrest and apoptosis. Moreover, NS398+TMZ counteracted the resistance in T98G preventing the TMZ-induced COX-2, \u03b2-catenin, MGMT, and SOX-2 up-regulation.<\/jats:p>","DOI":"10.3390\/ijms23031545","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T05:26:17Z","timestamp":1643433977000},"page":"1545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines"],"prefix":"10.3390","volume":"23","author":[{"given":"Francesca","family":"Lombardi","sequence":"first","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5907-7078","authenticated-orcid":false,"given":"Francesca Rosaria","family":"Augello","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Artone","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitilda Karoli","family":"Gugu","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9923-5445","authenticated-orcid":false,"given":"Maria Grazia","family":"Cifone","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Cinque","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7027-2691","authenticated-orcid":false,"given":"Paola","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Department of Life, Health & Environmental Sciences, University of L\u2019Aquila, Building Delta 6, Coppito, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1124\/pr.117.014944","article-title":"Current Challenges and Opportunities in Treating Glioblastoma","volume":"70","author":"Shergalis","year":"2018","journal-title":"Pharmacol. 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