{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T18:03:09Z","timestamp":1772301789272,"version":"3.50.1"},"reference-count":31,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Industry Department of the Government of Navarra, Spain","award":["PI054, PI059"],"award-info":[{"award-number":["PI054, PI059"]}]},{"DOI":"10.13039\/501100004587","name":"Instituto de salud Carlos III","doi-asserted-by":"publisher","award":["Miguel Servet II Program"],"award-info":[{"award-number":["Miguel Servet II Program"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Navarrabiomed-Fundaci\u00f3n Miguel Servet","award":["Postdoctoral fellowship to P.A."],"award-info":[{"award-number":["Postdoctoral fellowship to P.A."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The majority of glioblastoma (GBM) patients require the administration of dexamethasone (DEXA) to reduce brain inflammation. DEXA activates the glucocorticoid receptor (GR), which can consequently crosstalk with the mineralocorticoid receptor (MR). However, while GR signaling is well studied in GBM, little is known about the MR in brain tumors. We examined the implication of the MR in GBM considering its interplay with DEXA. Together with gene expression studies in patient cohorts, we used human GBM cell lines and patient-derived glioma stem cells (GSCs) to assess the impact of MR activation and inhibition on cell proliferation, response to radiotherapy, and self-renewal capacity. We show that in glioma patients, MR expression inversely correlates with tumor grade. Furthermore, low MR expression correlates with poorer survival in low grade glioma while in GBM the same applies to classical and mesenchymal subtypes, but not proneural tumors. MR activation by aldosterone suppresses the growth of some GBM cell lines and GSC self-renewal. In GBM cells, the MR antagonist spironolactone (SPI) can promote proliferation, radioprotection and cooperate with DEXA. In summary, we propose that MR signaling is anti-proliferative in GBM cells and blocks the self-renewal of GSCs. Contrary to previous evidence obtained in other cancer types, our results suggest that SPI has no compelling anti-neoplastic potential in GBM.<\/jats:p>","DOI":"10.3390\/ijms222111656","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:51:36Z","timestamp":1635465096000},"page":"11656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma"],"prefix":"10.3390","volume":"22","author":[{"given":"Paula","family":"Aldaz","sequence":"first","affiliation":[{"name":"Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad P\u00fablica de Navarra (UPNA), 31008 Pamplona, Spain"},{"name":"Health Research Institute of Navarre (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaya","family":"Fern\u00e1ndez-Celis","sequence":"additional","affiliation":[{"name":"Health Research Institute of Navarre (IdiSNA), 31008 Pamplona, Spain"},{"name":"Cardiovascular Translational Research Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad P\u00fablica de Navarra (UPNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"L\u00f3pez-Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Health Research Institute of Navarre (IdiSNA), 31008 Pamplona, Spain"},{"name":"Cardiovascular Translational Research Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad P\u00fablica de Navarra (UPNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6349-2442","authenticated-orcid":false,"given":"Imanol","family":"Arozarena","sequence":"additional","affiliation":[{"name":"Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad P\u00fablica de Navarra (UPNA), 31008 Pamplona, Spain"},{"name":"Health Research Institute of Navarre (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: A state of the science review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro. Oncol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1586\/ecp.11.1","article-title":"Corticosteroids in brain cancer patients: Benefits and pitfalls","volume":"4","author":"Dietrich","year":"2011","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1093\/brain\/aww046","article-title":"Corticosteroids compromise survival in glioblastoma","volume":"139","author":"Pitter","year":"2016","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fan, Z., Sehm, T., Rauh, M., Buchfelder, M., Eyupoglu, I.Y., and Savaskan, N.E. (2014). Dexamethasone Alleviates Tumor-Associated Brain Damage and Angiogenesis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093264"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aldaz, P., Auzmendi-Iriarte, J., Dur\u00e1ntez, M., Lasheras-Otero, I., Carrasco-Garcia, E., Zelaya, M., Bragado, L., Ol\u00edas-Arjona, A., Ega\u00f1a, L., and Sampr\u00f3n, N. (2021). Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma. Cancers, 13.","DOI":"10.3390\/cancers13020361"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrm.2016.152","article-title":"Glucocorticoid receptor control of transcription: Precision and plasticity via allostery","volume":"18","author":"Weikum","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ibarrola, J., Garaikoetxea, M., Garcia-Pe\u00f1a, A., Matilla, L., Jover, E., Bonnard, B., Cuesta, M., Fern\u00e1ndez-Celis, A., Jaisser, F., and L\u00f3pez-Andr\u00e9s, N. (2020). Beneficial Effects of Mineralocorticoid Receptor Antagonism on Myocardial Fibrosis in an Experimental Model of the Myxomatous Degeneration of the Mitral Valve. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155372"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.steroids.2014.08.014","article-title":"Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis","volume":"91","year":"2014","journal-title":"Steroids"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s000590050024","article-title":"Aldosterone and myocardial fibrosis in heart failure","volume":"25","author":"Brilla","year":"2000","journal-title":"Herz"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1093\/eurheartj\/eht187","article-title":"Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, double-blind trial","volume":"34","author":"Pitt","year":"2013","journal-title":"Eur. Hear. J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tiberio, L., Nascimbeni, R., Villanacci, V., Casella, C., Fra, A., Vezzoli, V., Furlan, L., Meyer, G., Parrinello, G., and Baroni, M.D. (2013). The Decrease of Mineralcorticoid Receptor Drives Angiogenic Pathways in Colorectal Cancer. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059410"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jeong, Y., Xie, Y., Xiao, G., Behrens, C., Girard, L., Wistuba, I.I., Minna, J.D., and Mangelsdorf, D. (2010). Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer. PLoS Med., 7.","DOI":"10.1371\/journal.pmed.1000378"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101410","DOI":"10.32527\/2019\/101410","article-title":"The Role of Mineralocorticoid Receptor Signaling in Genitourinary Cancers","volume":"6","author":"Nagata","year":"2019","journal-title":"Nucl. Recept. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1093\/neuonc\/now247","article-title":"GlioVIs data portal for visualization and analysis of brain tumor expression datasets","volume":"19","author":"Bowman","year":"2017","journal-title":"Neuro-Oncology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40169-018-0211-8","article-title":"Combination therapy to checkmate Glioblastoma: Clinical challenges and advances","volume":"7","author":"Ghosh","year":"2018","journal-title":"Clin. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1101\/gad.261982.115","article-title":"Cancer stem cells in glioblastoma","volume":"29","author":"Lathia","year":"2015","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nature11287","article-title":"A restricted cell population propagates glioblastoma growth after chemotherapy","volume":"488","author":"Chen","year":"2012","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1172\/JCI89587","article-title":"Overcoming therapeutic resistance in glioblastoma: The way forward","volume":"127","author":"Osuka","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1038\/s41388-018-0654-9","article-title":"Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response","volume":"38","author":"Gold","year":"2019","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sanomachi, T., Suzuki, S., Togashi, K., Sugai, A., Seino, S., Okada, M., Yoshioka, T., Kitanaka, C., and Yamamoto, M. (2019). Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs. Cancers, 11.","DOI":"10.3390\/cancers11101550"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5689","DOI":"10.1093\/nar\/gku217","article-title":"A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair","volume":"42","author":"Shahar","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gabbard, R., Hooopes, R., and Kemp, M. (2020). Spironolactone and XPB: An old drug with a new molecular target. Biomolecules, 10.","DOI":"10.3390\/biom10050756"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/hep.27940","article-title":"Mineralocorticoid receptor suppresses cancer progression and the Warburg effect by modulating the miR-338-3p-PKLR axis in hepatocellular carcinoma","volume":"62","author":"Nie","year":"2015","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Shiota, M., Fujimoto, N., Kashiwagi, E., and Eto, M. (2019). The Role of Nuclear Receptors in Prostate Cancer. Cells, 8.","DOI":"10.3390\/cells8060602"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6825","DOI":"10.1002\/jcp.26550","article-title":"Low NR3C2 levels correlate with aggressive features and poor prognosis in non-distant metastatic clear-cell renal cell carcinoma","volume":"233","author":"Zhao","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5879","DOI":"10.21873\/anticanres.13792","article-title":"Cytoplasmic Mineralocorticoid Receptor Expression Predicts Dismal Local Relapse-free Survival in Non-triple-negative Breast Cancer","volume":"39","author":"Jukkola","year":"2019","journal-title":"Anticancer. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1007\/s11605-007-0234-8","article-title":"Underexpression of Mineralocorticoid Receptor in Colorectal Carcinomas and Association with VEGFR-2 Overexpression","volume":"11","author":"Alvarado","year":"2007","journal-title":"J. Gastrointest. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"De La Rocha, A.M.A., Bertoni, H.L., Guruceaga, E., Gonzalez-Huarriz, M., Martinez-Velez, N., Xipell, E., Fueyo, J., Gomez-Manzano, C., and Alonso, M.M. (2016). Analysis of SOX2-Regulated Transcriptome in Glioma Stem Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163155"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1158\/1535-7163.MCT-14-0810","article-title":"MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide","volume":"14","author":"Erice","year":"2015","journal-title":"Mol. Cancer Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11656\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:53Z","timestamp":1760167313000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":31,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111656"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111656","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,28]]}}}