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Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis

ABSTRACT: Adaptation to acidosis has been reported to induce a shift towards fatty acid metabolism. We observed that conditioned medium of HCT, FaDu and SiHa adapted to acidosis (pH6.5) induced higher lipolysis of primary subcutaneous and mesenteric adipocytes compared to cancer cells maintained at pH7.4. In order to identify the prolipolytic factors induced by acidosis, we examined the differences between cancer cells adapted to pH6.5 and those maintained at pH7.4 by RNA sequencing. Cancer cells adapted to pH6.5 showed profound alterations in their gene expression compared with cancer cells maintained at pH7.4. Here, we focused on predicted secreted genes. We determined that 84 altered genes predicted to be secreted proteins overlapped between the 3 cancer cell lines, 24 of which were overexpressed. The role of these overexpressed genes was determined in vitro. We studied their role in inducing adipocyte lipolysis and in the depletion of adipose tissue observed in cancer cachexia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253054 | GEO | 2024/04/05

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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Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis

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