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Horm Metab Res 2021; 53(02): 124-131
DOI: 10.1055/a-1322-2943
Endocrine Research

Role of the Mevalonate Pathway in Adrenocortical Tumorigenesis

Helena Panteliou Lima-Valassi
1   Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Antonio Marcondes Lerario
2   Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Luciana Ribeiro Montenegro
1   Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Maria Candida Barisson Villares Fragoso
2   Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
3   Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Madson Queiroz Almeida
2   Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
3   Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Berenice Bilharinho Mendonca
1   Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
2   Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
,
Chin Jia Lin
4   Laboratório de Patologia Molecular LIM/22, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Abstract

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<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<0.05). However, cholesterol synthesis blockage did not show the same effect on cell viability. Low expression of TSPO , StAR, 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.

Key words

adrenocortical tumor - mevalonate pathway - steroidogenesis - cholesterol - steroids


Publication History

Received: 18 November 2019

Accepted: 20 November 2020

Article published online:
11 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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