Expression of PIK3CA WT and mutant colon cancer cells grown with (+ Gln)or without glutamine (-Gln)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA659806 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We used human gene expression microarray to interrogate how glutamine deprivation differentially impact gene expession in isogenic PIK3CA mutant and WT cells.
2020-08-28 | GSE157024 | GEO
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.
2015-08-13 | E-GEOD-71981 | biostudies-arrayexpress
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance.
2015-08-13 | GSE71981 | GEO
Project description:Glutamine (gln) is an essential and versatile metabolite that feeds different cellular pathways and generates several derivatives. Alpha-ketoglutarate (aKG) is the gln derivative that feeds the TCA cycle, activates cellular growth, and is related to epigenetic changes. Despite gln importance, the specific role of gln – and not its derivatives – in gene expression is not clear. To address this question, U2OS cells were cultured in the presence of gln or its absence +/- aKG for 8 hours. Gln had an unique effect in the transcriptome of U2OS cells and the addition of aKG was not able to mimic the gln effect. In conclusion, gln affects gene expression independently of its derivative aKG.
2024-09-10 | GSE276327 | GEO
Project description:To understand the global effect of Gln on gene expression, we performed RNA-seq analysis to compare the gene expression profiles between 12-day-old Arabidopsis seedlings grown on 5 mM NH4NO3 and 5 mM Gln as the sole N source.
2022-12-10 | GSE206966 | GEO
Project description:Testing TCA concentrations of Diffuse Intrinsic Pontine Gliomas (DIPG) cellines with H3K27M mutations. Preliminary studies show H3K27M tumor cells are addicted to Gln for survival. Removal of Gln from media resulted in tumor cell death which was rescued by the addition of α-KG. These data show that Gln is taken up and metabolized by H3K27M tumor cells and that Gln derived α-KG is critical for the survival of these tumors. Interestingly, tumor cell death with Gln deprivation was similar to the effect of the JMJD3 inhibitor GSKJ4. Therefore, Gln derived α-KG may be required for both anaplerosis and to drive JMJD3 demethylation. We hypothesize that H3K27M tumors are reliant on α-KG that is derived from Gln to drive the TCA cycle and further decrease H3K27 methylation levels. Furthermore, inhibition of Gln metabolism may represent a novel therapeutic approach for tumors with this mutation. In this study, TCA cycle metabolomics are analyzed of H3K27M cells grown in regular glutamine media, glutamine free media, and glutamine free media with alpha-ketoglutarate.
2018-07-18 | ST001024 | MetabolomicsWorkbench
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. A factor that contributes to the poor prognosis of the disease is the complex tumor microenvironment (TME). The PDAC TME is composed of excessive fibrosis and desmoplasia, which creates a harsh environment resulting in hypoxia and altered nutrient availability. To promote survival and proliferation in this environment, PDAC cells can reprogram glutamine (Gln) metabolism. Previous studies have demonstrated that PDAC cells use Gln to support proliferation and redox balance. However, earlier attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and ultimately therapeutic resistance. Here, we hypothesized that using a Gln analogue, such as 6-Diazo-5-oxo-L-norleucine (DON), could broadly target Gln metabolism in PDAC and prevent rapid adaptation. Indeed, DON treatment led to a significant decrease in PDAC proliferation in a dose-dependent manner, as well as a profound reduction of various metabolites involved in central carbon and nucleotide metabolism, suggesting that DON creates a metabolic crisis. In addition, we observed a significant decrease in tumor growth in various in vivo models (syngeneic, immunodeficient) using DRP-104 (sirpiglenastat), a novel pro-drug version of DON that was designed to circumvent DON associated GI toxicity and allow the therapeutic exploration of broad Gln antagonism. Mechanistically, we found that ERK signaling is increased as a compensatory mechanism through the increased activity of receptor tyrosine kinases (RTKs). Combinatorial treatment of DRP-104 and Trametinib (MEK1/2) inhibitor led to a significant increase in survival in a syngeneic model PDAC. Taken together, these pre-clinical results suggest that broadly targeting Gln metabolism could provide a new therapeutic avenue for PDAC and that the combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
2023-08-01 | GSE236225 | GEO
Project description:Algal biofuel production requires an input of synthetic nitrogen fertilizer. Fertilizer synthesized via the Haber-Bosch process produces CO2 as a waste by-product and represents a substantial financial and energy investment. Reliance on synthetic fertilizer attenuates the environmental significance and economic viability of algae production systems. To lower fertilizer input, the waste streams of algal production systems can be recycled to provide alternative sources of nitrogen such as amino acids to the algae. The halophytic green alga Dunaliella viridis can use ammonium (NH4+) derived from the abiotic degradation of amino acids, and previously, supplementation of NH4+ from glutamine (GLN) degradation was shown to support acceptable levels of growth and increased neutral lipid production compared to nitrate. To understand the effect of glutamine-released NH4+ on algae growth and physiology, metabolite levels, growth parameters, and transcript profiles of D. viridis cultures were observed in a time course after transition from media containing nitrate as a sole N source to medium containing GLN, glutamate (GLU), or a N-depleted medium. Growth parameters were similar between GLN (NH4+) and nitrate supplemented cultures, however, metabolite data showed that the GLN supplemented cultures (NH4+) more closely resembled cultures under nitrogen starvation (N-depleted and GLU supplementation). Neutral lipid accumulation was the same in nitrate and glutamine-derived NH4+ cultures. However, glutamine-derived NH4+ caused a transcriptional response in the immediate hours after inoculation of the culture. The strong initial response of cultures to NH4+ changed over the course of days to closely resemble that of nitrogen starvation. These observations suggest that release of NH4+ from glutamine was sufficient to maintain growth, but not high enough to trigger a cell transition to a nitrogen replete state. Comparative transcript profiling of the nitrogen-starved and nitrate-supplied cultures show an overall downregulation of fatty acid synthesis and a shift to starch synthesis and accumulation. The results indicate that a continuous, amino acid derived slow release of NH4+ to algae cultures could reduce the amount of synthetic nitrogen needed for growth, but optimization is needed to balance nitrogen starvation and cell division.
2018-03-30 | GSE111548 | GEO
Project description:Glutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy. We comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD. Patients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, “hot” immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells. This study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.
2022-07-31 | GSE209973 | GEO
Project description:By a transcriptome analysis using RNA sequencing in H1299 cells, a non-small cell lung cancer cell line (NSCLC), we determined the response of lipogenic genes to absence vs. presence of glutamine (Gln) or glucose (Gluc). We found that neither glutamine nor glucose alone was able to activate the expression of genes regulating fatty acid and cholesterol synthesis, and uptake, including SREBF1, SREBF2, ACLY, ACACA, FASN, SCD1, HMGCR and LDLR, as compared to absence of both. And, activation of lipogenic genes required the presence of both glutamine and glucose, but SCAP gene expression was not affected by either glutamine or glucose. The RNA sequencing analysis in H1299 cells also confirmed that ammonia, similarly to glutamine, significantly activated the expression of genes controlling the fatty acid and cholesterol synthesis pathways as compared to glucose alone. This study detemines the intrinsic molecular connection between glutamine, glucose and lipid synthesis.
2022-04-30 | GSE199089 | GEO