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

Nicholas C. Wolff, Renée M. McKay, James Brugarolas

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Glucocorticoids induce apoptosis in lymphocytes and are commonly used to treat hematologic malignancies. However, they are also associated with significant adverse effects and their molecular mechanism of action is not fully understood. Glucocorticoid treatment induces expression of the mTORC1 inhibitor Regulated in Development and DNA Damage Response 1 (REDD1), also known as DNA-Damage Inducible Transcript 4 (DDIT4), and mTORC1 inhibition may distinguish glucocorticoid-sensitive from glucocorticoid-resistant acute lymphoblastic leukemia (ALL). Interestingly, REDD1 induction was impaired in glucocorticoid-resistant ALL cells and inhibition of mTORC1 using rapamycin restored glucocorticoid sensitivity. These data suggest that REDD1 may be essential for the response of ALL cells to glucocorticoids. To further investigate the role of REDD1, we evaluated the effects of glucocorticoids on primary thymocytes from wild-type and REDD1-deficient mice. Glucocorticoidmediated apoptosis was blocked by a glucocorticoid receptor antagonist and by an inhibitor of transcription, which interfered with REDD1 induction and mTORC1 inhibition. However, REDD1 ablation had no effect on glucocorticoid-induced mTORC1 inhibition and apoptosis in thymocytes ex vivo. Overall, these data not only demonstrate the contextual differences of downstream signaling following glucocorticoid treatment but also provide a better mechanistic understanding of the role of REDD1.

Original languageEnglish (US)
Pages (from-to)867-877
Number of pages11
JournalMolecular Cancer Research
Volume12
Issue number6
DOIs
StatePublished - 2014

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Thymocytes
Glucocorticoids
DNA Damage
Apoptosis
Precursor Cell Lymphoblastic Leukemia-Lymphoma
mechanistic target of rapamycin complex 1
Glucocorticoid Receptors
Hematologic Neoplasms
Sirolimus
Lymphocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes. / Wolff, Nicholas C.; McKay, Renée M.; Brugarolas, James.

In: Molecular Cancer Research, Vol. 12, No. 6, 2014, p. 867-877.

Research output: Contribution to journalArticle

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