Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?

Abstract

Regulated in Development and DNA Damage Response 1 (REDD1)/DNA Damage-Induced Transcript 4 (DDIT4) is an immediate early response gene activated by different stress conditions, including growth factor depletion, hypoxia, DNA damage, and stress hormones, i.e., glucocorticoids. The most known functions of REDD1 are the inhibition of proliferative signaling and the regulation of metabolism via the repression of the central regulator of these processes, the mammalian target of rapamycin (mTOR). The involvement of REDD1 in cell growth, apoptosis, metabolism, and oxidative stress implies its role in various pathological conditions, including cancer and inflammatory diseases. Recently, REDD1 was identified as one of the central genes mechanistically involved in undesirable atrophic effects induced by chronic topical and systemic glucocorticoids widely used for the treatment of blood cancer and inflammatory diseases. In this review, we discuss the role of REDD1 in the regulation of cell signaling and processes in normal and cancer cells, its involvement in the pathogenesis of different diseases, and the approach to safer glucocorticoid receptor (GR)-targeted therapies via a combination of glucocorticoids and REDD1 inhibitors to decrease the adverse atrophogenic effects of these steroids.

DDIT4 promotes malignancy of head and neck squamous cell carcinoma

“…In addition, hypoxia can also contribute to an immunosuppressive TME network 38 . Previous studies have reported DDIT4 as a downstream molecular target of HIF‐1a 12 . Upregulation of DDIT4 is also reported to potentially inhibit HIF‐1a through a negative feedback loop, reduce ROS levels and suppress tumorigenesis via a mTORC1‐independent pathway 42 .…”

“…DDIT4, also named as REDD1, is expressed under stress conditions, including oxidative stress, endoplasmic reticulum stress and hypoxia, and regulates the processes of cell proliferation, differentiation, and metabolism 11,12 . The major effect of DDIT4 is produced by inhibiting the cell‐growth regulator mTORC1, including serine/threonine kinases mTOR and mLST8, and raptor protein 13,14 .…”

“…The major effect of DDIT4 is produced by inhibiting the cell‐growth regulator mTORC1, including serine/threonine kinases mTOR and mLST8, and raptor protein 13,14 . mTORC1 will be activated in response to nutrients and mitogens, and functions as a coordinator for various cellular processes such as proliferation, differentiation, and induction of autophagy 12,15 . Recent studies have demonstrated significant involvement of DDIT4 in several tumor types 16 .…”

“…5,9,10 DDIT4, also named as REDD1, is expressed under stress conditions, including oxidative stress, endoplasmic reticulum stress and hypoxia, and regulates the processes of cell proliferation, differentiation, and metabolism. 11,12 The major effect of DDIT4 is produced by inhibiting the cell-growth regulator mTORC1, including serine/threonine kinases mTOR and mLST8, and raptor protein. 13,14 mTORC1 will be activated in response to nutrients and mitogens, and functions as a coordinator for various cellular processes such as proliferation, differentiation, and induction of autophagy.…”

“…13,14 mTORC1 will be activated in response to nutrients and mitogens, and functions as a coordinator for various cellular processes such as proliferation, differentiation, and induction of autophagy. 12,15 Recent studies have demonstrated significant involvement of DDIT4 in several tumor types. 16 Du et al report that DDIT4 boosts the proliferation of gastric cancer cells and induces tumorigenesis both in vitro and in vivo.…”