Hirsch 2012 PloS One

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Hirsch A, Hahn D, Kempná P, Hofer G, Mullis PE, Nuoffer JM, Flück CE (2012) Role of AMP-activated protein kinase on steroid hormone biosynthesis in adrenal NCI-H295R cells. PLoS One 7:e30956.

» PMID: 22295121 Open Access

Hirsch A, Hahn D, Kempna P, Hofer G, Mullis PE, Nuoffer JM, Flueck CE (2012) PLoS One

Abstract: Regulation of human androgen biosynthesis is poorly understood. However, detailed knowledge is needed to eventually solve disorders with androgen dysbalance. We showed that starvation growth conditions shift steroidogenesis of human adrenal NCI-H295R cells towards androgen production attributable to decreased HSD3B2 expression and activity and increased CYP17A1 phosphorylation and 17,20-lyase activity. Generally, starvation induces stress and energy deprivation that need to be counteracted to maintain proper cell functions. AMP-activated protein kinase (AMPK) is a master energy sensor that regulates cellular energy balance. AMPK regulates steroidogenesis in the gonad. Therefore, we investigated whether AMPK is also a regulator of adrenal steroidogenesis. We hypothesized that starvation uses AMPK signaling to enhance androgen production in NCI-H295R cells. We found that AMPK subunits are expressed in NCI-H295 cells, normal adrenal tissue and human as well as pig ovary cells. Starvation growth conditions decreased phosphorylation, but not activity of AMPK in NCI-H295 cells. In contrast, the AMPK activator 5-aminoimidazole-4-carboxamide (AICAR) increased AMPKα phosphorylation and increased CYP17A1-17,20 lyase activity. Compound C (an AMPK inhibitor), directly inhibited CYP17A1 activities and can therefore not be used for AMPK signaling studies in steroidogenesis. HSD3B2 activity was neither altered by AICAR nor compound C. Starvation did not affect mitochondrial respiratory chain function in NCI-H295R cells suggesting that there is no indirect energy effect on AMPK through this avenue. In summary, starvation-mediated increase of androgen production in NCI-H295 cells does not seem to be mediated by AMPK signaling. But AMPK activation can enhance androgen production through a specific increase in CYP17A1-17,20 lyase activity. Keywords: Human adrenal NCI-H295R cells, Starvation, Steroidogenesis, Pig ovary cells

O2k-Network Lab: CH Bern Nuoffer JM

Labels: MiParea: Respiration, Comparative MiP;environmental MiP, mt-Medicine  Pathology: Cancer 

Organism: Human, Pig  Tissue;cell: Other cell lines  Preparation: Intact cells, Permeabilized cells  Enzyme: Complex I, Complex II;succinate dehydrogenase  Regulation: Substrate  Coupling state: ROUTINE, ET  Pathway: N, S, NS  HRR: Oxygraph-2k