Genotype-specific cortisol production associated with Cushing's syndrome adenoma with PRKACA mutations

Mol Cell Endocrinol. 2021 Dec 1:538:111456. doi: 10.1016/j.mce.2021.111456. Epub 2021 Sep 11.

Abstract

The intracellular molecular mechanisms underlying the genotype of cortisol-producing adenoma (CPA) have not been fully determined. We analyzed gene expressions in CPA and the human adrenocortical cell line (HAC15 cells) with PRKACA mutation. Clustering analysis using a gene set associated with responses to cAMP revealed the possible differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. The levels of STAR, CYP11A1, CYP17A1, CYP21A2, and FDX1 transcripts and cortisol levels per unit area in PRKACA mutant CPAs were significantly higher than those in GNAS mutant CPAs. PRKACA mutations led to an increase in steroidogenic enzyme expression and cortisol production in HAC15 cells. Transcriptome analysis revealed differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. Cortisol production in PRKACA mutant CPAs is increased by the cAMP-PKA signaling pathway-mediated upregulation of steroidogenic enzymes transcription. The intracellular molecular mechanisms underlying these processes would be notably important in PRKACA mutant CPAs.

Keywords: Cortisol; Cushing's syndrome; Gene expression; Genotype; PRKACA.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoma / genetics*
  • Adenoma / metabolism
  • Adult
  • Aged
  • Cell Line, Tumor
  • Chromogranins / genetics*
  • Cluster Analysis
  • Cushing Syndrome / genetics*
  • Cushing Syndrome / metabolism
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Hydrocortisone / metabolism
  • Male
  • Middle Aged
  • Mutation*
  • RNA-Seq
  • beta Catenin / genetics*

Substances

  • CTNNB1 protein, human
  • Chromogranins
  • beta Catenin
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs
  • Hydrocortisone