DNA damage response induced by Etoposide promotes steroidogenesis via GADD45A in cultured adrenal cells

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Mimi Tamamori-Adachi1, Akane Koga2,3, Takao Susa2

  • 1Department of Biochemistry, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-8605, Japan. madachi@med.teikyo-u.ac.jp.

Scientific Reports
|June 27, 2018
PubMed

Insights

Genotoxic stress, like DNA damage, triggers glucocorticoid production in adrenal cells independently of the usual ACTH pathway. This novel mechanism involves GADD45A and the p38MAPK pathway, offering new insights into steroidogenesis.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cellular Biology

Background:

  • Glucocorticoid production is typically regulated by adrenocorticotropic hormone (ACTH) through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway.
  • The impact of aging on steroidogenesis and potential alternative regulatory pathways remain largely unexplored.

Purpose of the Study:

  • To investigate whether non-ACTH-mediated pathways can induce steroidogenesis in adrenal cells.
  • To elucidate the role of genotoxic stress in regulating glucocorticoid production.
  • To identify key molecular mediators involved in stress-induced steroidogenesis.

Main Methods:

  • Utilized human adrenocortical H295R cells exposed to low-dose etoposide (EP) to induce genotoxic stress and DNA damage (marked by γH2AX).
  • Analyzed gene expression of stress-associated and steroidogenesis-related genes, including GADD45A.
  • Performed immunofluorescence for GADD45A localization, metabolite assays for glucocorticoid production, and knockdown studies using small interfering RNA (siRNA).
  • Investigated the involvement of p38MAPK and PKA pathways using specific inhibitors.

Main Results:

  • Genotoxic stress induced by etoposide promoted steroidogenesis in a cell-autonomous manner.
  • Upregulation of GADD45A and steroidogenesis-related genes was observed in DNA-damaged cells.
  • EP-treated cells showed increased glucocorticoid production and secretion.
  • GADD45A knockdown significantly inhibited EP-induced steroidogenesis.
  • p38MAPK inhibition suppressed EP-stimulated steroidogenesis, while PKA inhibition did not.

Conclusions:

  • DNA damage itself can promote steroidogenesis through novel, non-ACTH-mediated pathways.
  • GADD45A is a crucial mediator in the steroidogenic processes triggered by genotoxic stress.
  • The p38MAPK pathway, not PKA, is involved in this alternative steroidogenesis mechanism.
  • These findings reveal an unprecedented pathway for steroidogenesis in the adrenal cortex.

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