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GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation

ABSTRACT: GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation

PROVIDER: PRJNA1166203 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30825900_1.fastq.gz	Fastqsanger.gz
	SRR30825900_2.fastq.gz	Fastqsanger.gz
	SRR30825901_1.fastq.gz	Fastqsanger.gz
	SRR30825901_2.fastq.gz	Fastqsanger.gz
	SRR30825902_1.fastq.gz	Fastqsanger.gz

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GCN2-SLC7A11 axis coordinates autophagy, cell cycle and apoptosis and regulates cell growth in retinoblastoma upon arginine deprivation

Project description:Background: Arginine deprivation was shown previously to inhibit retinoblastoma cell proliferation and induce cell death in vitro. However, the mechanisms by which retinoblastoma cells respond to arginine deprivation remain to be elucidated. Methods: Human derived retinoblastoma cell lines Y79 and WERI-Rb-1 were exposed to arginine depletion, and the effects on inhibiting cell growth and survival were evaluated. The study investigated potential mechanisms, including autophagy, cell cycle arrest, and apoptosis. Moreover, the roles of GCN2 and mTOR signaling pathways in these processes were examined. Results: We demonstrated that arginine deprivation effectively inhibited the growth of retinoblastoma cells in vitro. This treatment caused an increase in autophagic response. Additionally, we found that prolonged arginine shortage induced G2 cell cycle arrest and was accompanied by an increase in early apoptotic cells. Importantly, arginine depletion also caused an activation of GCN2 and an inhibition of mTOR signaling. We also discovered that the activation of SLC7A11 was regulated by GCN2 upon arginine deprivation. Knockdown of SLC7A11 rendered retinoblastoma cells partially resistant to arginine deprivation. Furthermore, we found that knockdown of GCN2 led to a decrease in autophagic response in WERI-Rb-1 cells and arrested more cells in S phase, which was accompanied by fewer apoptotic cells. Moreover, knockdown of GCN2 caused constant expression of ATF4, phosphorylation of 70S6K, and 4E-BP1 regardless of arginine deprivation. Conclusions: Collectively, our findings suggest that the GCN2-SLC7A11 axis regulates cell growth and survival upon arginine deprivation through coordinating autophagy, cell cycle arrest, and apoptosis in retinoblastoma cells. This work paves the way for the development of a novel treatment for retinoblastoma.

2024-10-28 | GSE278276 | GEO

Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

Project description:We analyzed the transcriptomes of Wild-type and GCN2-deficient mouse embryonic stem cells after 3h of arginine or leucine starvation.

2024-01-01 | GSE195470 | GEO

ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition

Project description:The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we found that the 20μM low arginine condition, as present in multiple TMEs, confers upon activated T cells Treg-like immunosuppressive capacities. In vivo mouse tumor models and human scRNA-Seq datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low-arginine activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

2024-02-25 | GSE256171 | GEO

CD200+ CD8 T Cell Generated through Arginine Deprivation to Activate Macrophage Cross-presentation and Improve Anti-Tumor Immunity [ATAC-Seq]

Project description:Arginine is indispensable for both tumor progression and the function of immune cells, yet how arginine deprivation within the tumor microenvironment shapes anti-tumor immunity has remained unclear. In this study, we established an in vivo arginine-restriction model using a diet lacking arginine, which significantly suppressed tumor growth and activated global anti-tumor immune responses. Mechanistically, arginine deprivation triggered the integrated stress response in CD8+ T cells via the GCN2–cREL signaling axis, leading to elevated CD200 expression. These CD200+ CD8+ T cells in turn enhanced the antigen cross-presentation capacity of tumor-associated macrophages through CD200–CD200R interactions, forming a cooperative immune network that reinforced anti-tumor activity. Moreover, this arginine deprivation–induced cellular synergy improved the therapeutic efficacy of immunotherapy in colorectal cancer models. We further conducted a single-arm phase I clinical trial (NCT07038044), which demonstrated that an arginine-free diet is both feasible and safe for modulating systemic immunity in patients. Together, our findings provide a new conceptual framework for understanding the role of arginine in reshaping the tumor immune microenvironment and highlight arginine restriction as a promising and clinically translatable anti-tumor strategy.

2025-12-01 | GSE311145 | GEO

CD200+ CD8 T Cell Generated through Arginine Deprivation to Activate Macrophage Cross-presentation and Improve Anti-Tumor Immunity [RNA-Seq]

2025-12-01 | GSE311146 | GEO

CD200+ CD8 T Cell Generated through Arginine Deprivation to Activate Macrophage Cross-presentation and Improve Anti-Tumor Immunity [scRNA-Seq]

2025-12-01 | GSE311149 | GEO

CD200+ CD8 T Cell Generated through Arginine Deprivation to Activate Macrophage Cross-presentation and Improve Anti-Tumor Immunity [RNA-Seq 2]

2025-12-01 | GSE311148 | GEO

Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

Project description:Transcriptomic analysis of arginine- and leucine-starved mouse embryonic stem cells (Wild type and GCN2-deficient)

| PRJNA800758 | ENA

LncRNA SLC7A11-AS1 suppresses ferroptosis in hepatocellular carcinoma to promote tumorigenesis

Project description:LncRNAs are playing essential roles in epigenetic regulation, mRNA translation, and protein modification. However, the function of SLC7A11-AS1, an antisense lncRNA derived from the solute carrier family 7 member 11 (SLC7A11) gene, remains incompletely known. In this study, we utilized shRNA technology to knock down SLC7A11-AS1 in HepG2 cells, aiming to investigate the role of SLC7A11-AS1 in hepatocellular carcinoma. RNA-seq results revealed that there were 2536 differentially expressed genes upon SLC7A11-AS1 knockdown.

2024-07-17 | GSE244762 | GEO

GCN2 regulates paclitaxel-induced neuropathic pain

Project description:Neuropathic pain is a significant clinical challenge affecting patients treated with the chemotherapeutic paclitaxel. Current therapeutic options for paclitaxel-induced neuropathy are limited due to an incomplete understanding of its molecular mechanisms. Here, we demonstrate a critical role for the Integrated Stress Response (ISR) in paclitaxel-induced neuropathic pain. Paclitaxel robustly activates the ISR specifically in dorsal root ganglion (DRG) neurons via the upstream kinase GCN2. Activation of GCN2 alone is sufficient to sensitize DRG neurons to depolarization and produce pain-like behaviors in vivo. Critically, paclitaxel-induced DRG neuron sensitization and behavioral mechanical and cold hypersensitivity require GCN2 signaling. Finally, paclitaxel treatment reduces global tRNA charging and abundance, providing a mechanistic basis for GCN2 activation. These findings position GCN2 and the ISR as promising therapeutic targets for the management of paclitaxel-induced neuropathic pain.

2025-11-12 | GSE291827 | GEO

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