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Combined with Gefitinib Overcomes Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

ABSTRACT: Combined with Gefitinib Overcomes Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

PROVIDER: PRJNA1122184 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29348310_1.fastq.gz	Fastqsanger.gz
	SRR29348310_2.fastq.gz	Fastqsanger.gz
	SRR29348311_1.fastq.gz	Fastqsanger.gz
	SRR29348311_2.fastq.gz	Fastqsanger.gz
	SRR29348312_1.fastq.gz	Fastqsanger.gz

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Combined with Gefitinib Overcomes Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

Project description:Glutamine is a major energy source for tumor cells and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. Here, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) inhibited bladder cancer cells in vitro in several ways. In addition, we observed a remarkable inhibition of tumor growth in bladder cancer-bearing mice using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade up-regulates PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combinatorial treatment with JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade. This reversal resulted in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings suggested that broad targeting of glutamine metabolism could represent a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.

2024-08-08 | GSE269520 | GEO

Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

Project description:Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

| EGAS00001006334 | EGA

Human Non-Small Cell Lung Cancer cells: Control vs gefitinib treated cells

Project description:Total gene expression difference after treatment gefitinib for 24 h compared to control NSCLCs To determine which proteins are responsible for the differences in glutamine metabolism in response to the gefitinib treatment between gefitinib-sensitive and gefitinib-resistant cells

2017-09-13 | GSE103780 | GEO

Analysis of gene expression change by gefitinib treatment in gefitinib sensitive PC9 and resistant PC9.

2012-07-01 | GSE38302 | GEO

Analysis of gene expression change by gefitinib treatment in gefitinib sensitive PC9 and resistant PC9.

Project description:We established a gefitinib-resistant cell line (PC-9GR), by serial exposure of gefitinib to PC-9, an originally gefitinib-sensitive lung cancer cell line (PC-9na), for long period.We collected total RNA from both PC-9 and PC-9GR and examined mRNA expression profile, comprehensively. Gefitinib induced gene expression was measured in human lung cancer cell line was measured at 48 hours after exposure to 1uM Gefitinib.

2012-06-30 | E-GEOD-38302 | biostudies-arrayexpress

Combined treatment with N-acetylcysteine and gefitinib overcomes drug resistance to gefitinib in NSCLC cell line.

Project description:We aimed to explore the molecular substrate underlying EGFR-TKI resistance and investigate the effects of N-acetylcysteine (NAC) on reversing EGFR-TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK-8 assay, combination index (CI) method, matrigel invasion assay, wound-healing assay, flow cytometry, western blot, and quantitative real-time PCR (qRT-PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR-TKI resistance in non-small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI < 1). Matrigel invasion assay and wound healing assay demonstrated a decrease in migration and invasion ability of PC-9/GR cells after NAC and gefitinib treatment. Flow cytometry displayed enhanced apoptosis in the combination group. Western blot and qRT-PCR revealed that increased E-cadherin and decreased vimentin in the combination group. When PP2 was administered with gefitinib, the same effects were seen. Our findings suggest that NAC could restore the sensitivity of gefitinib-resistant NSCLC cells to gefitinib via suppressing Src activation and reversing epithelial-mesenchymal transition.

| S-EPMC7013061 | biostudies-literature

Gefitinib sensitivity in NSCLC cell lines

Project description:Eleven NSCLC cell lines with widely divergent gefitinib sensitivities were compared using gene expression. Genes associated with gefitinib response were used to classify additional NSCLC lines with unknown gefitnib sensitivity. A subset of the test set data was tested for gefitinib sensitivity, and results correlated strongly with the gene expression-based predictions All eleven training set lines, and seven test set lines had both HGU133A and B chips done, while other test set lines had only HGU133As. Keywords: cell response comparison

2006-08-31 | GSE4342 | GEO

miRNA expression of gefitinib-resistant cell lines

Project description:To identify novel miRNAs involved in acquired EGFR TKI resistance in NSCLC, genome-wide miRNA expression analysis was performed in gefitinib-resistant sub-cell lines and gefitinib-sensitive parental cell lines.

2018-02-21 | GSE110815 | GEO

Gefitinib treatment in human EGFR-driven-Gefitinib resistant tumoral cell line

Project description:Gefitinib treatment in human EGFR-driven-Gefitinib resistant tumoral cell line

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SLC38A2 and glutamine signaling in cDC1 dictate anti-tumor immunity [array]

Project description:Cancer cells evade T-cell-mediated killing through poorly understood mechanisms of tumour–immune interactions. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1), mediate T-cell priming and therapeutic efficacy against tumours. Besides pattern recognition receptors (PRRs), how DC functions are shaped by other environmental cues remains incompletely defined. Nutrients are emerging mediators of adaptive immunity, but whether nutrients impact DC function or innate–adaptive cell communication is largely unresolved. Here, we establish glutamine as an intercellular metabolic checkpoint to mediate tumour–cDC1 crosstalk and license cDC1 functionality for activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T-cell immunity, and also overcomes therapeutic resistance to checkpoint blockade and T-cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1 compete for glutamine uptake via transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid for promoting cDC1 function, by signalling via FLCN to impinge upon TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner, and phenocopies SLC38A2 deficiency by abrogating anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1 that underpins tumour immunoevasion, and reveal glutamine acquisition and signalling in cDC1 as limiting events for DC activation and putative targets for cancer treatment.

2023-05-24 | GSE210148 | GEO

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