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Impact of short- and long-term extracellular acidosis on gene expression of tumors in vitro and in vivo

ABSTRACT: Purpose: The aim of the study was to analyze the impact of acidic pHe on gene expression in two experimental tumor lines of the rat in vitro and in vivo. The results of short-term incubation (24 h) were compared to chronically acidosis-adapted cells (5 weeks). Methods: Gene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat. Cells were exposed to pH 7.4 and 6.6 for 24 h or 5 weeks. Experimental tumors were implanted in rats and control tumors were compared to tumors in which the glycolytic metabolism was intensified. Results: The analyses revealed that 147 genes were uniformly regulated in both cell lines (in vitro) and 79 genes in both experimental tumors after 24 h at low pH. 265 genes were uniformly regulated during long- and short-term exposure to low pH.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE162705 | GEO | 2021/01/02

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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Impact of short- and long-term extracellular acidosis on gene expression of tumors in vitro and in vivo

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