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REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes

Nicholas C Wolff1, Renée M McKay2, James Brugarolas3

  • 1Authors' Affiliations: Division of Hematology-Oncology, Department of Internal Medicine, Department of Developmental Biology, and the Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Molecular Cancer Research : MCR
|March 12, 2014
PubMed
Abstract

Insights

Glucocorticoids induce lymphocyte apoptosis but have side effects. REDD1 (Regulated in Development and DNA Damage Response 1) is induced by glucocorticoids, but its role in glucocorticoid resistance in leukemia is complex and context-dependent.

Area of Science:

  • Molecular mechanisms of cancer therapy
  • Cellular signaling pathways
  • Immunology and hematology

Background:

  • Glucocorticoids are vital for treating hematologic malignancies by inducing lymphocyte apoptosis.
  • Significant adverse effects and incompletely understood mechanisms limit their use.
  • Regulated in Development and DNA Damage Response 1 (REDD1) is an mTORC1 inhibitor induced by glucocorticoids, potentially differentiating sensitive from resistant leukemia.

Purpose of the Study:

  • To investigate the role of REDD1 in glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia (ALL).
  • To elucidate the molecular mechanisms underlying glucocorticoid action and REDD1's involvement.
  • To explore the contextual differences in downstream signaling following glucocorticoid treatment.

Main Methods:

  • Assessed REDD1 induction and its correlation with glucocorticoid sensitivity in ALL cells.
  • Utilized rapamycin to inhibit mTORC1 and evaluated its effect on glucocorticoid sensitivity.
  • Examined glucocorticoid effects on primary thymocytes from wild-type and REDD1-deficient mice.
  • Employed glucocorticoid receptor antagonists and transcription inhibitors to probe signaling pathways.

Main Results:

  • REDD1 induction was impaired in glucocorticoid-resistant ALL cells.
  • mTORC1 inhibition with rapamycin restored glucocorticoid sensitivity in resistant cells.
  • REDD1 ablation did not affect glucocorticoid-induced mTORC1 inhibition or apoptosis in ex vivo thymocytes.
  • Glucocorticoid-mediated apoptosis was blocked by receptor antagonism and transcription inhibition, which also interfered with REDD1 induction.

Conclusions:

  • REDD1's role in glucocorticoid response is context-dependent, showing differences between ALL cells and primary thymocytes.
  • These findings enhance mechanistic understanding of glucocorticoid action and REDD1 signaling.
  • Molecular insights are crucial for developing improved glucocorticoid analogs with better efficacy and reduced toxicity.

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