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Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility.

ABSTRACT: Metabolic reprogramming is required for tumors to meet the bioenergetic and biosynthetic demands of malignant progression. Numerous studies have established a causal relationship between oncogenic drivers and altered metabolism, most prominently aerobic glycolysis, which supports rapid growth and affects the tumor microenvironment. Less is known about how the microenvironment modulates cancer metabolism. In the present study, we found that low extracellular pH, a common feature of solid tumors, provoked PDAC cells to decrease glycolysis and become resistant to glucose starvation. This was accompanied by increased dependency on mitochondrial metabolism, in which long-chain fatty acids became a primary fuel source. Consistent with previous reports, low pH enhanced tumor cell invasiveness. A novel finding was that limiting PDAC metabolic flexibility by either suppression of oxidative phosphorylation capacity or the pharmacological inhibition of fatty-acid oxidation prevented invasion induced by low extracellular pH. Altogether, our results suggest for the first time that targeting fatty-acid oxidation may be a viable adjunct strategy for preventing metastatic progression of pancreatic cancer mediated by the acidic tumor compartment.

SUBMITTER: Shin SC

PROVIDER: S-EPMC9894376 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility.

Shin Simon C SC Thomas Divya D Radhakrishnan Prakash P Hollingsworth Michael A MA

Biochemical and biophysical research communications 20200218

Metabolic reprogramming is required for tumors to meet the bioenergetic and biosynthetic demands of malignant progression. Numerous studies have established a causal relationship between oncogenic drivers and altered metabolism, most prominently aerobic glycolysis, which supports rapid growth and affects the tumor microenvironment. Less is known about how the microenvironment modulates cancer metabolism. In the present study, we found that low extracellular pH, a common feature of solid tumors, ...[more]

PMID: 32081432

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Project description:BackgroundThe tumor microenvironment is characterized by regions of hypoxia and acidosis which are linked to poor prognosis. This occurs due to an aberrant vasculature as well as high rates of glycolysis and lactate production in tumor cells even in the presence of oxygen (the Warburg effect), which weakens the spatial linkage between hypoxia and acidosis.MethodsFive different human squamous cell carcinoma cell lines (SiHa, FaDuDD, UTSCC5, UTSCC14 and UTSCC15) were treated with hypoxia, acidosis (pH 6.3), or a combination, and gene expression analyzed using microarray. SiHa and FaDuDD were chosen for further characterization of cell energetics and protein synthesis. Total cellular ATP turnover and relative glycolytic dependency was determined by simultaneous measurements of oxygen consumption and lactate synthesis rates and total protein synthesis was determined by autoradiographic quantification of the incorporation of 35S-labelled methionine and cysteine into protein.ResultsMicroarray analysis allowed differentiation between genes induced at low oxygen only at normal extracellular pH (pHe), genes induced at low oxygen at both normal and low pHe, and genes induced at low pHe independent of oxygen concentration. Several genes were found to be upregulated by acidosis independent of oxygenation. Acidosis resulted in a more wide-scale change in gene expression profiles than hypoxia including upregulation of genes involved in the translation process, for example Eukaryotic translation initiation factor 4A, isoform 2 (EIF4A2), and Ribosomal protein L37 (RPL37). Acidosis suppressed overall ATP turnover and protein synthesis by 50%. Protein synthesis, but not total ATP production, was also suppressed under hypoxic conditions. A dramatic decrease in ATP turnover (SiHa) and protein synthesis (both cell lines) was observed when hypoxia and low pHe were combined.ConclusionsWe demonstrate here that the influence of hypoxia and acidosis causes different responses, both in gene expression and in de novo protein synthesis, depending on whether the two factors induced alone or overlapping, and as such it is important for in vivo studies to take this into account.

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Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility.

Publications

Invasive phenotype induced by low extracellular pH requires mitochondria dependent metabolic flexibility.

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