Institute of Biomedical Sciences, Department of Anatomy, University of Sao Paulo, SP, Brazil.
Laboratory of Hormone and Molecular Genetic LIM/42, University of Sao Paulo, SP, Brazil.
Mol Cell Endocrinol. 2018 Jan 15;460:36-46. doi: 10.1016/j.mce.2017.06.027. Epub 2017 Jul 1.
The participation of aberrant receptors and intra-adrenal ACTH in hyperplastic tissue are considered mechanisms that regulate hypercortisolism in PMAH. Additionally, germline ARMC5 mutations have been described as the most frequent genetic abnormality found in patients diagnosed with PMAH. Previous functional studies analyzed ARMC5 role using H295R cells. Therefore, we investigated the role of ARMC5 in cell cultures obtained from PMAH nodules containing steroidogenic cells, aberrant receptors and intra-adrenal ACTH. ARMC5 silencing in non-mutated PMAH cell cultures decreased steroidogenesis-related genes and increased CCNE1 mRNA expression and proliferative capacity without affecting cell viability. Additionally, ARMC5 overexpression induced cell death in PMAH mutated cell cultures, thereby decreasing cell viability. We confirmed the role of ARMC5 as an important pro-apoptotic protein involved in PMAH-related steroidogenesis. We also report for the first time the involvement of ARMC5 in controlling proliferation and regulating cell cycle in PMAH cell cultures; these effects need to be explored further.
异常受体和肾上腺内 ACTH 的参与被认为是调节 PMAH 中皮质醇过多的机制。此外，胚系 ARMC5 突变已被描述为在诊断为 PMAH 的患者中发现的最常见的遗传异常。先前的功能研究使用 H295R 细胞分析了 ARMC5 的作用。因此，我们研究了 ARMC5 在含有类固醇生成细胞、异常受体和肾上腺内 ACTH 的 PMAH 结节细胞培养物中的作用。在非突变型 PMAH 细胞培养物中沉默 ARMC5 减少了与类固醇生成相关的基因，增加了 CCNE1 mRNA 的表达和增殖能力，而不影响细胞活力。此外，ARMC5 在 PMAH 突变细胞培养物中过表达诱导细胞死亡，从而降低细胞活力。我们证实了 ARMC5 作为一种参与 PMAH 相关类固醇生成的重要促凋亡蛋白的作用。我们还首次报道了 ARMC5 在控制增殖和调节 PMAH 细胞培养物细胞周期中的作用；这些作用需要进一步探索。
