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Transcriptional responses to TNF following HFol treatment of wild type and GCN2 depleted synoviocytes

ABSTRACT: We report the effects of Hfol on TNF induction of inflammatory genes in wild type cells versus cells depleted of GCN2 RNA-seq analysis of wild type or GCN2-depleted established fibroblast like synoviocytes (K4 cells) treated with TNFa in the presence or absence of Halofuginone (HF).

ORGANISM(S): Homo sapiens

PROVIDER: GSE145203 | GEO | 2020/03/22

REPOSITORIES: GEO

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Transcriptional responses to TNF following HFl treatment of primary rheumatoid arthritis fibroblast like synoviocytes (RA-FLS)

Project description:We report the effects of Hfol on TNF induction of inflammatory genes in wild type cells versus cells depleted of GCN2 RNA-seq analysis of primary rheumatoid arthritis fibroblast like synoviocytes (RA-FLS) treated with TNFa in the presence or absence of Halofuginone (HF).

2020-03-22 | GSE145204 | GEO

Transcriptional responses of wild-type and Gcn2-/- Th17 cells to halofuginone and rapamycin

Project description:This study was designed to evaluate similarities and differences between transcriptional responses of developing Th17 cells to the prolyl-tRNA synthetase inhibitor, halofuginone, and the mTOR inhibitor, rapamycin. Further comparisons between wild-type and Gcn2-/- Th17 cells allow for investigation into which gene modules regulated by halofuginone or rapamycin treatment require Gcn2. Murine CD4+ CD25- T cells were magnetically isolated from wild-type or Gcn2-/- T cells. These cells were activated through anti-CD3/ anti-CD28 antibodies and polarized into Th17 cells using TGFb plus IL-6. 10 nM halofuginone, 10 nM rapamycin, or vehicle control (DMSO) were added to cultures at the time of activation. Cells were harvested at 4, 18, or 72 hours post-activation and differentiation. RNA was isolated from each sample and used for microarray analysis. Each culture condition and time-point was repeated twice in independent experiments using cells isolated from different wild-type or Gcn2-/- mice. Vehicle versus halofuginone, vehicle versus rapamycin, halofuginone versus rapamycin. Gcn2-/- versus wild-type T cells treated with vehicle, halofuginone, or rapamycin.

2014-05-29 | E-GEOD-47478 | biostudies-arrayexpress

Transcriptional responses of wild-type and Gcn2-/- Th17 cells to halofuginone and rapamycin

2014-05-29 | GSE47478 | GEO

Transcriptional responses to TNF following HFol treatment of wild type and GCN2 depleted synoviocytes

Project description:Transcriptional responses to TNF following HFol treatment of wild type and GCN2 depleted synoviocytes

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Transcriptional responses of fibroblast like synoviocytes to TNFa in the presence or absence of Halofuginone (HF)

Project description:Transcriptional responses of fibroblast like synoviocytes to TNFa in the presence or absence of Halofuginone (HF)

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Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress

Project description:Here we report Total RNA seq and RiboSeq on MEF cells treated with halofuginone. Halofuginone is a competitive inhibitor of the Prolyl-tRNA synthetase that results in an accumulation of uncharged Prolyl-tRNA upon treatment that leads to an activation of the protein kinase Gcn2.

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Halofuginone, a tRNA-synthetase inhibitor, decreases bulk protein synthesis independently of the integrated stress response

Project description:The integrated stress response (ISR), a vital homeostatic pathway, is an emerging therapeutic target for a broad range of clinical indications. Halofuginone (HF) is a phase 2 clinical compound that induces the ISR by inhibiting the glutamyl-prolyl-tRNA synthetase (EPRS). Here we report that although HF induces the predicted canonical ISR adaptations consisting of attenuation of protein synthesis and gene expression reprogramming, the former surprisingly occurs independently of GCN2 and eIF2 phosphorylation. Proline supplementation rescues the observed HF-induced changes indicating that they result from an on-target effect due to inhibition of EPRS. We find that attenuation of translation initiation through GCN2-to-eIF2 signaling is not robust enough to prevent translation elongation defects caused by HF. Exploiting this vulnerability, we show that cancer cells presenting an increased proline dependency are sensitized to HF. This work provides novel insights on ISR signaling and a molecular framework to guide the targeted development of HF.

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Microarray profiling reveals Integrated Stress Response is activated by Halofuginone in mammary epithelial cells

Project description:The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFb signaling and activation of the AAR have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type. We report that HF modulation of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFß signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR). Our findings suggest a common mechanism underlying HF anti-fibrotic and anti-angiogenic effects in parenchymal cells and HF effects on Th17 differentiation. Moreover, our results point away from a central role of TGFb signaling in the HF mechanism of action and suggest a new approach to small molecule based regulation of the ECM transcriptional program in vivo. NMuMG mammary epithelial cells were treated with 10 nM Halofuginone or 10 nM MAZ1310 (a non-functional analog of Halofuginone used as a control) for 8 hours. Each treatment was performed in biological triplicate. Following RNA extraction, we used Phalanx Mouse Whole Genome OneArray to measure mRNA abundance of Halofuginone-treated and MAZ1310 control samples. Each array was performed in triplicate. Expression of transcripts in Halofuginone versus MAZ1310 treated cells was examined.

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Arabidopsis Wild-type vs. Gcn2 GT8350 mutant line.

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Ex vivo activation of the GCN2 pathway metabolically reprograms T cells leading to enhanced adoptive cell therapy

Project description:The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the General Control Non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Further characterization revealed that halo-treated CD8+ T cells increased expression of the large neutral amino acid (LNAA) transporter CD98 as well as the co-stimulatory marker 4-1BB. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into mice bearing well-established tumors led to robust tumor control and curative responses. Halo-treated T cells also synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halofuginone can enhance T cell metabolism, effector function and anti-tumor activity, with the potential to augment existing clinical immunotherapeutic approaches.

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