{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:45:38Z","timestamp":1791215138946,"version":"4.1.0"},"reference-count":40,"publisher":"The Endocrine Society","issue":"1","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Mammalian target of rapamycin (mTOR) inhibitors suppress adrenal cortical carcinoma cell proliferation and cortisol production; the relationship between mTOR and aldosterone production has not been examined.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>HAC15 cells were incubated with an mTOR activator and several inhibitors including AZD8055 (AZD) in the presence and absence of angiotensin II (AngII). The expression of rapamycin-sensitive adapter protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (Rictor), adaptor proteins of mTOR complex 1 and 2, respectively, were studied in the HAC15 cells and deleted by CRISPR\/gRNA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The mTOR inhibitors decreased aldosterone induced by AngII. Inhibition of mTOR by AZD significantly suppressed AngII-induced aldosterone and cortisol formation in a dose-dependent manner, whereas the mTOR activator MHY had no effect. AZD did not alter forskolin-induced aldosterone production showing that it is specific to the AngII signaling pathway. AngII-mediated ERK and mTOR activation were suppressed by AZD, along with a concomitant dose-dependent reduction of AngII-induced steroidogenic enzymes including steroidogenic acute regulatory protein, 3\u03b2-hydroxysteroid dehydrogenase-type 2, CYP17A1, and aldosterone synthase protein. Furthermore, mTOR components ribosomal protein S6 kinase (P70S6K) and protein kinase B phosphorylation levels were decreased by AZD. As mTOR exerts its main effects by forming complexes with adaptor proteins Raptor and Rictor, the roles of these individual complexes were studied. We found an increase in the phosphorylation of Raptor and Rictor by AngII and that their CRISPR\/gRNA-mediated knockdown significantly attenuated AngII-induced aldosterone and cortisol production.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>mTOR signaling has a critical role in transducing the AngII signal initiating aldosterone and cortisol synthesis in HAC15 cells and that inhibition of mTOR could be a therapeutic option for conditions associated with excessive renin\u2013angiotensin system-mediated steroid synthesis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/endocr\/bqac185","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T04:48:00Z","timestamp":1667364480000},"source":"Crossref","is-referenced-by-count":5,"title":["Mammalian Target of Rapamycin Inhibition Decreases Angiotensin II-Induced Steroidogenesis in HAC15 Human Adrenocortical Carcinoma Cells"],"prefix":"10.1210","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0753-3590","authenticated-orcid":false,"given":"Yusuf","family":"Ali","sequence":"first","affiliation":[{"name":"G. V. (Sonny) Montgomery, VA Medical Center , Jackson, MS , USA"},{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, MS , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4432-4950","authenticated-orcid":false,"given":"Elise P","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, MS , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9882-2082","authenticated-orcid":false,"given":"Celso E","family":"Gomez-Sanchez","sequence":"additional","affiliation":[{"name":"G. V. (Sonny) Montgomery, VA Medical Center , Jackson, MS , USA"},{"name":"Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, MS , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"issue":"2","key":"2023062011041184500_bqac185-B1","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.mce.2011.07.034","article-title":"Acute and chronic regulation of aldosterone production","volume":"350","author":"Hattangady","year":"2012","journal-title":"Mol Cell Endocrinol"},{"issue":"1","key":"2023062011041184500_bqac185-B2","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1210\/er.2010-0013","article-title":"The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders","volume":"32","author":"Miller","year":"2011","journal-title":"Endocr Rev"},{"issue":"2","key":"2023062011041184500_bqac185-B3","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1152\/physrev.00030.2003","article-title":"Control of aldosterone secretion: a model for convergence in cellular signaling pathways","volume":"84","author":"Spat","year":"2004","journal-title":"Physiol Rev"},{"issue":"11","key":"2023062011041184500_bqac185-B4","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1038\/ncb1183","article-title":"Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive","volume":"6","author":"Jacinto","year":"2004","journal-title":"Nat Cell Biol"},{"issue":"16","key":"2023062011041184500_bqac185-B5","doi-asserted-by":"publisher","first-page":"3343","DOI":"10.1242\/dev.058230","article-title":"An emerging role for TOR signaling in mammalian tissue and stem cell physiology","volume":"138","author":"Russell","year":"2011","journal-title":"Development"},{"issue":"2","key":"2023062011041184500_bqac185-B6","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"issue":"6","key":"2023062011041184500_bqac185-B7","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"2023062011041184500_bqac185-B8","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jbior.2019.03.003","article-title":"Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship","volume":"72","author":"Jhanwar-Uniyal","year":"2019","journal-title":"Adv Biol Regul"},{"issue":"3","key":"2023062011041184500_bqac185-B9","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/s1097-2765(02)00636-6","article-title":"Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control","volume":"10","author":"Loewith","year":"2002","journal-title":"Mol Cell"},{"issue":"4","key":"2023062011041184500_bqac185-B10","doi-asserted-by":"publisher","first-page":"e62399","DOI":"10.1371\/journal.pone.0062399","article-title":"The PI3K\/AKT\/mTOR signaling pathway is overactivated in primary aldosteronism","volume":"8","author":"Su","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"2023062011041184500_bqac185-B11","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1530\/ERC-11-0270","article-title":"The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells","volume":"19","author":"De Martino","year":"2012","journal-title":"Endocr Relat Cancer"},{"issue":"10","key":"2023062011041184500_bqac185-B12","doi-asserted-by":"publisher","first-page":"4703","DOI":"10.1210\/jc.2019-00563","article-title":"Treatment of primary aldosteronism with mTORC1 inhibitors","volume":"104","author":"Trinh","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2023062011041184500_bqac185-B13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1055\/s-0031-1298019","article-title":"Comparison of aldosterone production among human adrenocortical cell lines","volume":"44","author":"Wang","year":"2012","journal-title":"Horm Metab Res"},{"issue":"11","key":"2023062011041184500_bqac185-B14","doi-asserted-by":"publisher","first-page":"4542","DOI":"10.1210\/jc.2008-0903","article-title":"Development of an adrenocorticotropin-responsive human adrenocortical carcinoma cell line","volume":"93","author":"Parmar","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2023062011041184500_bqac185-B15","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1152\/physiolgenomics.00097.2004","article-title":"Angiotensin II early regulated genes in H295R human adrenocortical cells","volume":"19","author":"Romero","year":"2004","journal-title":"Physiol Genomics"},{"issue":"2","key":"2023062011041184500_bqac185-B16","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1210\/en.2004-0935","article-title":"Angiotensin II stimulates protein synthesis and inhibits proliferation in primary cultures of rat adrenal glomerulosa cells","volume":"146","author":"Otis","year":"2005","journal-title":"Endocrinology"},{"issue":"9","key":"2023062011041184500_bqac185-B17","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.3390\/cells10092376","article-title":"Transcriptomic response dynamics of human primary and immortalized adrenocortical cells to steroidogenic stimuli","volume":"10","author":"Wellman","year":"2021","journal-title":"Cells"},{"issue":"6","key":"2023062011041184500_bqac185-B18","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/0039-128x(87)90097-3","article-title":"The production of monoclonal antibodies against aldosterone","volume":"49","author":"Gomez-Sanchez","year":"1987","journal-title":"Steroids"},{"issue":"1-2","key":"2023062011041184500_bqac185-B19","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.mce.2013.11.022","article-title":"Development of monoclonal antibodies against human CYP11B1 and CYP11B2","volume":"383","author":"Gomez-Sanchez","year":"2014","journal-title":"Mol Cell Endocrinol"},{"key":"2023062011041184500_bqac185-B20","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.steroids.2017.08.011","article-title":"Development of monoclonal antibodies against the human 3\u03b2-hydroxysteroid dehydrogenase\/isomerase isozymes","volume":"127","author":"Gomez-Sanchez","year":"2017","journal-title":"Steroids"},{"issue":"4","key":"2023062011041184500_bqac185-B21","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1210\/en.2011-1733","article-title":"Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis","volume":"153","author":"Oki","year":"2012","journal-title":"Endocrinology"},{"issue":"1","key":"2023062011041184500_bqac185-B22","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1210\/en.2012-1557","article-title":"Angiotensin II and III metabolism and effects on steroid production in the HAC15 human adrenocortical cell line","volume":"154","author":"Oki","year":"2013","journal-title":"Endocrinology"},{"issue":"11","key":"2023062011041184500_bqac185-B23","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab146","article-title":"11\u03b2HSD2 Efficacy in preventing transcriptional activation of the mineralocorticoid receptor by corticosterone","volume":"5","author":"Ali","year":"2021","journal-title":"J Endocr Soc"},{"issue":"1-2","key":"2023062011041184500_bqac185-B24","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.jim.2006.07.027","article-title":"A cost effective non-commercial ECL-solution for Western blot detections yielding strong signals and low background","volume":"318","author":"Haan","year":"2007","journal-title":"J Immunol Methods"},{"issue":"3-4","key":"2023062011041184500_bqac185-B25","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/j.bbrc.2016.10.104","article-title":"MHY1485 activates mTOR and protects osteoblasts from dexamethasone","volume":"481","author":"Zhao","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"issue":"10","key":"2023062011041184500_bqac185-B26","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1111\/pin.12200","article-title":"Dissecting the molecular pathways of primary aldosteronism","volume":"64","author":"Nakamura","year":"2014","journal-title":"Pathol Int"},{"issue":"1","key":"2023062011041184500_bqac185-B27","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1158\/0008-5472.CAN-09-1751","article-title":"AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity","volume":"70","author":"Chresta","year":"2010","journal-title":"Cancer Res"},{"issue":"1","key":"2023062011041184500_bqac185-B28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in patients with systolic heart failure and mild symptoms","volume":"364","author":"Zannad","year":"2011","journal-title":"N Engl J Med"},{"issue":"1","key":"2023062011041184500_bqac185-B29","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1161\/HYPERTENSIONAHA.109.140988","article-title":"Efficacy of spironolactone therapy in patients with true resistant hypertension","volume":"55","author":"de Souza","year":"2010","journal-title":"Hypertension"},{"issue":"3","key":"2023062011041184500_bqac185-B30","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1002\/cphy.c130044","article-title":"The multifaceted mineralocorticoid receptor","volume":"4","author":"Gomez-Sanchez","year":"2014","journal-title":"Compr Physiol"},{"issue":"4","key":"2023062011041184500_bqac185-B31","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1161\/HYPERTENSIONAHA.117.10360","article-title":"Selective mineralocorticoid receptor cofactor modulation as molecular basis for Finerenone's antifibrotic activity","volume":"71","author":"Grune","year":"2018","journal-title":"Hypertension"},{"issue":"4","key":"2023062011041184500_bqac185-B32","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1530\/ERC-13-0112","article-title":"Characterization of the mTOR pathway in human normal adrenal and adrenocortical tumors","volume":"21","author":"De Martino","year":"2014","journal-title":"Endocr Relat Cancer"},{"issue":"4","key":"2023062011041184500_bqac185-B33","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1210\/en.2018-00989","article-title":"Aldosterone modulates the mechanistic target of rapamycin signaling in male mice","volume":"160","author":"Brooks","year":"2019","journal-title":"Endocrinology"},{"issue":"9","key":"2023062011041184500_bqac185-B34","doi-asserted-by":"publisher","first-page":"R144","DOI":"10.1530\/EC-19-0224","article-title":"The role of mTOR pathway as target for treatment in adrenocortical cancer","volume":"8","author":"De Martino","year":"2019","journal-title":"Endocr Connect"},{"issue":"2","key":"2023062011041184500_bqac185-B35","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s12022-017-9473-8","article-title":"Tissue expression and pharmacological in vitro analyses of mTOR and SSTR pathways in adrenocortical carcinoma","volume":"28","author":"Germano","year":"2017","journal-title":"Endocr Pathol"},{"issue":"15","key":"2023062011041184500_bqac185-B36","doi-asserted-by":"publisher","first-page":"3716","DOI":"10.3390\/cancers13153716","article-title":"Primary aldosteronism: metabolic reprogramming and the pathogenesis of aldosterone-producing adenomas","volume":"13","author":"Gong","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"3","key":"2023062011041184500_bqac185-B37","doi-asserted-by":"publisher","first-page":"E423","DOI":"10.1152\/ajpendo.00128.2005","article-title":"Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP","volume":"290","author":"Gambaryan","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"9","key":"2023062011041184500_bqac185-B38","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1172\/JCI34764","article-title":"Targeting AKT\/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model","volume":"118","author":"Kinkade","year":"2008","journal-title":"J Clin Invest"},{"issue":"6","key":"2023062011041184500_bqac185-B39","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation","volume":"36","author":"Mendoza","year":"2011","journal-title":"Trends Biochem Sci"},{"issue":"1","key":"2023062011041184500_bqac185-B40","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3892\/ijmm.2019.4407","article-title":"Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling","volume":"45","author":"Gao","year":"2020","journal-title":"Int J Mol Med"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqac185\/46938070\/bqac185.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/164\/1\/bqac185\/50653820\/bqac185.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/164\/1\/bqac185\/50653820\/bqac185.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T11:04:34Z","timestamp":1687259074000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqac185\/6793711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":40,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,11,14]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqac185","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,1,1]]},"published":{"date-parts":[[2022,11,2]]},"article-number":"bqac185"}}