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Tumor suppressor gene ARMC5 controls adrenal redox state through NRF1 turnover

Isadora P Cavalcante1, Marthe Rizk-Rabin1, Christopher Ribes1

  • 1Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.

Endocrine-Related Cancer
|August 30, 2022
PubMed
Abstract

Insights

The ARMC5 tumor suppressor regulates adrenal cell survival and steroid production by controlling cellular redox balance. This study reveals ARMC5

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a cause of Cushing's syndrome linked to ARMC5 mutations.
  • The precise functions of ARMC5 in adrenal cells, particularly its role in steroidogenesis and cell viability, remain largely unknown.
  • Tumor suppressor genes are known to influence intracellular redox responses, impacting cell signaling.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ARMC5 regulates adrenocortical cell function.
  • To investigate ARMC5's role in managing cellular redox homeostasis and its impact on steroidogenesis.
  • To determine how ARMC5 influences cell viability and its sensitivity to ferroptosis.

Main Methods:

  • Inactivation of ARMC5 in adrenocortical cells.
  • Analysis of reactive oxygen species (ROS) scavenging actors, including superoxide dismutases (SOD) and peroxiredoxins (PRDX).
  • Investigation of the transcriptional regulator NRF1, its ubiquitylation, and half-life.
  • Assessment of adrenocortical steroidogenesis and the involvement of the p38 pathway.
  • Evaluation of cell sensitivity to ferroptosis.

Main Results:

  • ARMC5 inactivation led to increased expression of ROS-scavenging enzymes (SOD, PRDX) via enhanced NRF1 activity.
  • ARMC5 was found to regulate NRF1 ubiquitination and stability.
  • ARMC5 deficiency altered steroidogenesis through p38 pathway activation.
  • Loss of ARMC5 decreased sensitivity to ferroptosis, enhancing cell viability.

Conclusions:

  • ARMC5 functions as a critical regulator of redox homeostasis in adrenocortical cells.
  • ARMC5 controls adrenal steroidogenesis and cell survival pathways.
  • Understanding ARMC5's role provides insights into PBMAH pathogenesis and potential therapeutic targets.
Keywords:
ARMC5NRF1adrenocortical tumorscell redox state

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