Lactic acidosis triggers starvation response with distinct metabolic profiles
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PROVIDER: PRJNA120737 | ENA |
REPOSITORIES: ENA
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Project description:[1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for different length of time. We used microarrays to examine the genomic programs of cells incubated under lactic acidosis for different length of time [2] Metabolic profiling: MCF7 cells were exposed to control condition, 25mM lactic acidosis, glucose deprivation (zero glucose) and hypoxia (1% oxygen level). [3] Mouse study: Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. Wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs and the RNAs from cells were extracted with MiRVana kit (Ambion) and applied to Affymetrix 430A mouse chips We used microarrays to examine the genomic programs of cells incubated under different microenvironmental stresses. [1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for 1, 4, 12 and 24 hours. [2] Metabolic profiling: MCF7 cells were exposed to lactic acidosis, glucose deprivation and hypoxia for 4hours. [3] wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs.
2010-09-27 | E-GEOD-19123 | biostudies-arrayexpress
Project description:[1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for different length of time. We used microarrays to examine the genomic programs of cells incubated under lactic acidosis for different length of time [2] Metabolic profiling: MCF7 cells were exposed to control condition, 25mM lactic acidosis, glucose deprivation (zero glucose) and hypoxia (1% oxygen level). [3] Mouse study: Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. Wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs and the RNAs from cells were extracted with MiRVana kit (Ambion) and applied to Affymetrix 430A mouse chips We used microarrays to examine the genomic programs of cells incubated under different microenvironmental stresses.
2010-09-27 | GSE19123 | GEO
Project description:Human Mammalian Epithelial Cells (HMEC) were exposed to different environmental stresses, including hypoxia, lactic acidosis, the combination of hypoxia and lactic acidosis, lactosis , as well as acidosis. We used microarrays to examine the genomic programs of cells incubated under different microenvironments. Experiment Overall Design: HMEC cells were exposed to different environmental stresses and RNAs were extracted and put on Affymetrix microarrays. We gathered RNAs from cells grown in regular media (control), lactic acidosis, hypoxia, the combinatino of lactic acidosis and hypoxia, lactosis, as well as acidosis.
2009-01-13 | E-GEOD-9649 | biostudies-arrayexpress
Project description:To understand the effect of lactic acidosis in cholangiocarcinoma cell line. Cells were cultured in different conditions: lactic acidosis, lactosis, acidosis and control. We found that lactic acidosis promoted aggressiveness of cancer cells and reprograming of metabolic.
2022-10-12 | GSE215085 | GEO
Project description:Human Mammalian Epithelial Cells (HMEC) were exposed to different environmental stresses, including hypoxia, lactic acidosis, the combination of hypoxia and lactic acidosis, lactosis , as well as acidosis. We used microarrays to examine the genomic programs of cells incubated under different microenvironments. Keywords: different environmental stresses
2008-12-18 | GSE9649 | GEO
Project description:Lactic acidosis and hypoxia are two prominent tumor microenvironmental stresses that are both known to exert important influences on gene expression and phenotypes of cancer cells. But very little is known about the cross-talk and interaction between these two stresses. We performed gene expression analysis of MCF7 cells exposed to lactic acidosis, hypoxia and combined lactic acidosis and hypoxia. We found the hypoxia response elicited under hypoxia was mostly abolished upon simultaneous exposure to lactic acidosis. The repression effects are due to loss of HIF-1α protein synthesis under lactic acidosis. In addition, we showed lactic acidosis strongly synergizes with hypoxia to activate the unfold protein response (UPR) and inflammation response which are highly similar to amino acid deprivation responses (AAR). The statistical factor analysis of hypoxia and lactic acidosis responses indicated that ATF4 locus, an important activator in the UPR/AAR pathway, is amplified in subsets of breast tumors and cancer cell lines. Varying ATF4 levels dramatically affect the ability to survive the post-stress recovery from hypoxia and lactic acidosis and may suggest its selection of ATF4 amplification in human cancers. These data suggest that lactic acidosis interacts with hypoxia by both inhibiting the canonical hypoxia response and while activating the UPR and inflammation response. Gain of ATF4 locus may offer survival advantages to allow successful adaptation to frequent fluctuations of oxygen and acidity in tumor microenvironment. Collectively, our studies have provided linkage between the short-term transcriptional responses to the long term selection of the DNA copy number alterations (CNAs) under tumor microenvironmental stresses. RNAs from MCF7 cells exposed to control condition (ambient air ~21% O2, no lactate and neutral pH), lactic acidosis (ambient air, 10 mM Lactate and pH 6.7), hypoxia (1% pO2, no lactate and neutral pH) and the combined lactic acidosis and hypoxia (1% pO2, 10 mM Lactate and pH 6.7) condition for 24 hours were extracted by miRVana kits (Ambion) and hybridized to Affymetrix Human genome 133A 2.0 arrays with standard protocol.
2012-02-27 | E-GEOD-29406 | biostudies-arrayexpress
Project description:Lactic acidosis and hypoxia are two prominent tumor microenvironmental stresses that are both known to exert important influences on gene expression and phenotypes of cancer cells. But very little is known about the cross-talk and interaction between these two stresses. We performed gene expression analysis of MCF7 cells exposed to lactic acidosis, hypoxia and combined lactic acidosis and hypoxia. We found the hypoxia response elicited under hypoxia was mostly abolished upon simultaneous exposure to lactic acidosis. The repression effects are due to loss of HIF-1α protein synthesis under lactic acidosis. In addition, we showed lactic acidosis strongly synergizes with hypoxia to activate the unfold protein response (UPR) and inflammation response which are highly similar to amino acid deprivation responses (AAR). The statistical factor analysis of hypoxia and lactic acidosis responses indicated that ATF4 locus, an important activator in the UPR/AAR pathway, is amplified in subsets of breast tumors and cancer cell lines. Varying ATF4 levels dramatically affect the ability to survive the post-stress recovery from hypoxia and lactic acidosis and may suggest its selection of ATF4 amplification in human cancers. These data suggest that lactic acidosis interacts with hypoxia by both inhibiting the canonical hypoxia response and while activating the UPR and inflammation response. Gain of ATF4 locus may offer survival advantages to allow successful adaptation to frequent fluctuations of oxygen and acidity in tumor microenvironment. Collectively, our studies have provided linkage between the short-term transcriptional responses to the long term selection of the DNA copy number alterations (CNAs) under tumor microenvironmental stresses.
2012-02-27 | GSE29406 | GEO
Project description:Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers.
| S-EPMC2937306 | biostudies-literature
Project description:MondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.
2019-01-23 | GSE117622 | GEO
Project description:Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production
| PRJNA482669 | ENA