{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T16:19:37Z","timestamp":1758817177018},"reference-count":29,"publisher":"Georg Thieme Verlag KG","issue":"02","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway, which generates cholesterol and non-sterol compounds such as isoprenoid, which are involved in key steps of tumorigenesis such as cell growth and proliferation. Our aim was to evaluate the role of the mevalonate pathway in adrenocortical tumors (ACTs). Expression pattern of HMGCR, FDFT1, LDLR, SCARB1, StAR, TSPO, CYP11A1, CYP11B1, CYP17A1, CYP21A1, and HSD3B1 genes, involved in the mevalonate pathway and steroidogenesis, was quantified by real-time RT-PCR in 46 ACT [14 adenomas (ACA) and 11 carcinomas (ACC) from adults and 13 ACA and 8 ACC from pediatric patients]. Effects of the mevalonate pathway inhibition on NCI-H295A cell viability was assessed by colorimetric assay. HMGCR was overexpressed in most adult ACT. The expression of TSPO, STAR, CYP11B1, CYP21A1, and HSD3B1 in adult ACC was significantly lower than in ACA (p&lt;0.05). Regarding pediatric ACT, the expression of genes involved in steroidogenesis was not different between ACA and ACC. Inhibition of isoprenoid production significantly decreased the viability of NCI-H295A cells (p&lt;0.05). However, cholesterol synthesis blockage did not show the same effect on cell viability. Low expression of TSPO\n,\nStAR, CYP11B1, CYP21A1, and HSD3B1 characterized a signature of adult ACCs. Our data suggest that HMGCR overexpression in adult ACC might lead to intracellular isoprenoid accumulation and cell proliferation. Therefore, the mevalonate pathway is a potential target for ACC treatment.<\/jats:p>","DOI":"10.1055\/a-1322-2943","type":"journal-article","created":{"date-parts":[[2020,12,12]],"date-time":"2020-12-12T00:52:04Z","timestamp":1607734324000},"page":"124-131","source":"Crossref","is-referenced-by-count":1,"title":["Role of the Mevalonate Pathway in Adrenocortical Tumorigenesis"],"prefix":"10.1055","volume":"53","author":[{"given":"Helena Panteliou","family":"Lima-Valassi","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM\/42, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Marcondes","family":"Lerario","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luciana Ribeiro","family":"Montenegro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM\/42, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Candida Barisson Villares","family":"Fragoso","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Instituto do C\u00e2ncer do Estado de S\u00e3o Paulo, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madson Queiroz","family":"Almeida","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Instituto do C\u00e2ncer do Estado de S\u00e3o Paulo, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berenice Bilharinho","family":"Mendonca","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM\/42, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chin Jia","family":"Lin","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Patologia Molecular LIM\/22, Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, 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for oncogenic mutations in the adrenocorticotropon receptor gene in human adrenocortical neoplasms","volume":"80","author":"A Latronico","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1055\/s-2007-981476","article-title":"The molecular pathogenesis of childhood adrenocortical tumors","volume":"39","author":"M Q Almeida","year":"2007","journal-title":"Horm Metab Res"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.mce.2011.09.040","article-title":"Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults","volume":"351","author":"A M Faria","year":"2012","journal-title":"Mol Cell Endocrinol"},{"key":"ref7","first-page":"6762","article-title":"Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors","volume":"61","author":"C Gicquel","year":"2001","journal-title":"Cancer Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/1472-6823-4-3","article-title":"Assessment of the role of transcript for GATA-4 as a marker of unfavorable outcome in human adrenocortical neoplasms","volume":"4","author":"A S Barbosa","year":"2004","journal-title":"BMC Endocr Disord"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/PL00013183","article-title":"Gelatinase A and membrane-type 1 matrix metalloproteinase mRNA: Expressed in adrenocortical cancers but not in adenomas","volume":"23","author":"M Kjellman","year":"1999","journal-title":"World J Surg"},{"key":"ref10","first-page":"4219","article-title":"Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy","volume":"56","author":"M Kjellman","year":"1996","journal-title":"Cancer Res"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1023\/A:1008257530919","article-title":"Adrenocortical carcinoma","volume":"8","author":"C Gicquel","year":"1997","journal-title":"Ann Oncol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"9330","DOI":"10.1073\/pnas.161479898","article-title":"An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma","volume":"98","author":"R C Ribeiro","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"4970","DOI":"10.1210\/jcem.86.10.7957","article-title":"An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors","volume":"86","author":"A C Latronico","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"ref14","first-page":"1","article-title":"Cholesterol metabolism and colon cancer","volume":"17","author":"S A Broitman","year":"1993","journal-title":"Prog Food Nutr Sci"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/S0005-2736(03)00016-6","article-title":"Role of cholesterol in lipid raft formation: lessons from lipid model systems","volume":"1610","author":"J R Silvius","year":"2003","journal-title":"Biochim Biophys Acta"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/j.bbapap.2006.09.017","article-title":"Hydrophobic modifications of Ras proteins by isoprenoid groups and fatty acids--More than just membrane anchoring","volume":"1764","author":"M Pechlivanis","year":"2006","journal-title":"Biochim Biophys Acta"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s00018-005-5298-6","article-title":"Isoprenylated proteins","volume":"63","author":"S J McTaggart","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1210\/jc.2018-01394","article-title":"Comparison of seated with recumbent saline suppression testing for the diagnosis of primary aldosteronism","volume":"103","author":"M Stowasser","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1182\/blood.V63.3.690.690","article-title":"Increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis in freshly isolated hairy cell leukemia cells","volume":"63","author":"S Yachnin","year":"1984","journal-title":"Blood"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1182\/blood.V84.8.2689.2689","article-title":"Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells","volume":"84","author":"S Vitols","year":"1994","journal-title":"Blood"},{"key":"ref21","first-page":"55","article-title":"Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549","author":"F Bennis","year":"1993","journal-title":"Int J Cancer"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1097\/00000478-200307000-00001","article-title":"Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients","volume":"27","author":"J A Wieneke","year":"2003","journal-title":"Am J Surg Pathol"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"P Chomczynski","year":"1987","journal-title":"Anal Biochem"},{"key":"ref24","first-page":"365","article-title":"Transcription of the human genes for cytochrome P450scc and P450c17 is regulated differently in human adrenal NCI-H295 cells than in mouse adrenal Y1 cells","volume":"82","author":"H Rodriguez","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1210\/jc.2004-1075","article-title":"Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy","volume":"90","author":"F de Fraipont","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/(SICI)1096-8628(19991203)87:4<349::AID-AJMG13>3.0.CO;2-N","article-title":"Autosomal XX sex reversal caused by duplication of SOX9","volume":"87","author":"B Huang","year":"1999","journal-title":"Am J Med Genet"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cccn.2005.04.003","article-title":"Cholesteryl esters in malignancy","volume":"359","author":"M R Tosi","year":"2005","journal-title":"Clin Chim Acta"},{"key":"ref28","doi-asserted-by":"crossref","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":"W L Miller","year":"2011","journal-title":"Endocr Rev"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1210\/jc.2009-1383","article-title":"Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"95","author":"M Bidet","year":"2010","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Hormone and Metabolic 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