Glucocorticoid Elevation of Dexamethasone-induced Gene 2 (Dig2/RTP801/REDD1) Protein Mediates Autophagy in Lymphocytes

Abstract

Glucocorticoid hormones, including dexamethasone, induce apoptosis in lymphocytes and consequently are used clinically as chemotherapeutic agents in many hematologic malignancies. Dexamethasone also induces autophagy in lymphocytes, although the mechanism is not fully elucidated. Through gene expression analysis, we found that dexamethasone induces the expression of a gene encoding a stress response protein variously referred to as Dig2, RTP801, or REDD1. This protein is reported to inhibit mammalian target of rapamycin (mTOR) signaling. Because autophagy is one outcome of mTOR inhibition, we investigated the hypothesis that Dig2/RTP801/REDD1 elevation contributes to autophagy induction in dexamethasone-treated lymphocytes. In support of this hypothesis, RNAimediated suppression of Dig2/RTP801/REDD1 reduces mTOR inhibition and autophagy in glucocorticoid-treated lymphocytes. We observed similar results in Dig2/Rtp801/Redd1 knock-out murine thymocytes treated with dexamethasone. Dig2/RTP801/REDD1 knockdown also leads to increased levels of dexamethasone-induced cell death, suggesting that Dig2/ RTP801/REDD1-mediated autophagy promotes cell survival. Collectively, these findings demonstrate for the first time that elevation of Dig2/RTP801/REDD1 contributes to the induction of autophagy.

Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells

“…35 Dex also promoted autophagy by inhibiting IP 3 -mediated calcium signaling 36 or by increasing Dig2 protein. 16 Together, based on diverse pharmacological effects of Dex, multiple signaling pathway implicated in Dex-induced autophagy regulation. Combination Dex and inhibitor of specific signaling targets (such as Akt and Dig2) would improve lymphoid malignancy therapy.…”

“…Dig2 knockdown led to increased cell death during Dex treatment. 16 Similarly, induction of autophagy contributed to prolonged survival of Bcl-2 positive murine lymphoma cells following Dex treatment. Inhibition of autophagy by 3-MA enhanced cytotoxicity of Dex in Bcl-2-positive cancer cells.…”

Chromosome 19 open reading frame 80 is upregulated by thyroid hormone and modulates autophagy and lipid metabolism

“…For instance, glucocorticoid hormones induce a stress response gene, DDIT4 (DNA-damageinducible transcript 4), to repress MTOR signaling and promote autophagy in lymphocytes and osteocytes. 31,32 Moreover, serum deficiency induces both autophagy and apoptosis in mammary epithelial cells. Meanwhile, another study has reported that the autophagy pathway is suppressed by IGF1 [insulin-like growth factor 1 (somatomedin C)] and EGF (epidermal growth factor), but activated by 17β-estradiol and progesterone.…”

REDD1/DDIT4-Independent mTORC1 Inhibition and Apoptosis by Glucocorticoids in Thymocytes

“…Interestingly, recent reports have shown that rapamycin, an mTORC1 inhibitor, can sensitize GC-resistant CEM cells to dexamethasone indicating that inhibiting mTORC1 signaling may be sufficient to bypass resistance (25, 26). Inasmuch as REDD1 is induced by dexamethasone (27–29) and that forced overexpression of REDD1 is sufficient to inhibit mTORC1 (17), we hypothesized that differential sensitivity of CEM cells to GCs may be dependent on REDD1.…”