REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses

Barroca, Vilma; Henry, Elia; Dechamps, Nathalie; Renou, Laurent; Chaintreuil, Paul; Kulkarni, Ravi S.; Devanand, Saiyirami; Jacquel, Arnaud; Robert, Guillaume; Auberger, Patrick; Pflumio, Françoise; Arcangeli, Marie-Laure

doi:10.1038/s41375-022-01609-x

Cited by 2 publications

(2 citation statements)

References 15 publications

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“…DDIT4 inhibits mTOR activation by interacting with the TSC1/2 complex [ 26 ]. Enhancing DDIT4 expression has been shown to be an effective strategy for inhibiting the growth of a variety of tumours by repressing mTOR activity and the phosphorylation of the downstream protein S6 [ 58 – 64 ]. Among the four common target genes of the NR modulators in osteosarcoma cells, DDIT4 has the highest expression level and its expression exhibits greatest fold change after treatment with the modulators.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway

et al. 2023

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Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway

et al. 2023

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“…Then ROS levels have to be controlled to avoid HSC exhaustion. 48 , 49 Recently, low mitochondrial activity has been associated with the high stemness potential of expanded HSC. 50 We showed that Tempol effects are mediated at least in part by the inhibition of p38MAPK pathway and the increase of VEGFα signaling during culture.…”

Section: Discussionmentioning

confidence: 99%

The Antioxidant TEMPOL Protects Human Hematopoietic Stem Cells From Culture-Mediated Loss of Functions

Henry,

Picou,

Barroca

et al. 2023

Stem Cells Translational Medicine

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In a steady state, hematopoietic stem cells (HSC) exhibit very low levels of reactive oxygen species (ROS). Upon stress, HSC get activated and enter into proliferation and differentiation process to ensure blood cell regeneration. Once activated, their levels of ROS increase, as messengers to mediate their proliferation and differentiation programs. However, at the end of the stress episode, ROS levels need to return to normal to avoid HSC exhaustion. It was shown that antioxidants can prevent loss of HSC self-renewal potential in several contexts such as aging or after exposure to low doses of irradiation suggesting that antioxidants can be used to maintain HSC functional properties upon culture-induced stress. Indeed, in humans, HSC are increasingly used for cell and gene therapy approaches, requiring them to be cultured for several days. As expected, we show that a short culture period leads to drastic defects in HSC functional properties. Moreover, a switch of HSC transcriptional program from stemness to differentiation was evidenced in cultured HSC. Interestingly, cultured-HSC treated with 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO or Tempol) exhibited a higher clonogenic potential in secondary colony forming unit cell (CFU-C) assay and higher reconstitution potential in xenograft model, compared to untreated cultured-HSC. By transcriptomic analyses combined with serial CFU-C assays, we show that Tempol, which mimics superoxide dismutase, protects HSC from culture-induced stress partly through VEGFα signaling. Thus, we demonstrate that adding Tempol leads to the protection of HSC functional properties during ex vivo culture.

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REDD1 is a gatekeeper of murine hematopoietic stem cell functions during stress responses

Cited by 2 publications

References 15 publications

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway

Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway

The Antioxidant TEMPOL Protects Human Hematopoietic Stem Cells From Culture-Mediated Loss of Functions

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