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Acidosis and hypoxia responsive gene expression profiles of U87MG glioblastoma cells

ABSTRACT: In this study, we aimed to elucidate the molecular underpinnings of metabolic adaptation in the stressed TME. LD accumulation has been well documented in glioblastoma (GBM), a prototypical high-grade brain malignancy characterized by severe acidosis, hypoxia, and metabolic heterogeneity. Unexpectedly, we observed a prominent enrichment of pathways related to glycocalyx remodeling in the LD-rich niche of patient tumors, particularly those involving CS biosynthesis and PG regulation. These findings prompted us to explore how glycan remodeling intersects with lipid metabolism in GBM and whether this interaction contributes to tumor stress adaptation. Our results highlight an acidosis-induced glycan program with potential as a metabolic vulnerability, offering new therapeutic avenues for targeting the lipid-stressed niche in aggressive tumors. We used microarrays to evaluate transcriptional signature of acidosis adaptation, short-term acidosis (pH 6.4) or short-term hypoxia in U87MG GBM cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300765 | GEO | 2026/01/04

REPOSITORIES: GEO

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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-1Î± 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.

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Acidosis and hypoxia responsive gene expression profiles of U87MG glioblastoma cells

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