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

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.

Automated summary

The intracellular molecular mechanisms underlying the genotype of cortisol-producing adenoma (CPA) with PRKACA mutation were investigated in this study. Analysis revealed that PRKACA mutations led to increased steroidogenic enzyme expression and cortisol production, distinguishing them from GNAS and CTNNB1 mutant CPAs. These findings highlight the importance of the cAMP-PKA signaling pathway in regulating cortisol production in PRKACA mutant CPAs.