Role of the Mevalonate Pathway in Adrenocortical Tumorigenesis

Helena Panteliou Lima-Valassi; Antonio Marcondes Lerario; Luciana Ribeiro Montenegro; Maria Candida Barisson Villares Fragoso; Madson Queiroz Almeida; Berenice Bilharinho Mendonca; Chin Jia Lin

doi:10.1055/a-1322-2943

Hormone and Metabolic Research, Inhaltsverzeichnis

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

Endocrine Research

Role of the Mevalonate Pathway in Adrenocortical Tumorigenesis

Authors

Helena Panteliou Lima-Valassi

¹Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Antonio Marcondes Lerario

²Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Luciana Ribeiro Montenegro

¹Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Maria Candida Barisson Villares Fragoso

²Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

³Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Madson Queiroz Almeida

²Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

³Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Berenice Bilharinho Mendonca

¹Laboratório de Hormônios e Genética Molecular LIM/42, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

²Unidade de Endocrinologia do Desenvolvimento & Unidade de Suprarrenal, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Chin Jia Lin

⁴Laboratório de Patologia Molecular LIM/22, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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

Volltext

Referenzen

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