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

Simon C Shin; Divya Thomas; Prakash Radhakrishnan; Michael A Hollingsworth

doi:10.1016/j.bbrc.2020.02.018

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

Biochem Biophys Res Commun. 2020 Feb 18:S0006-291X(20)30284-9. doi: 10.1016/j.bbrc.2020.02.018. Online ahead of print.

Authors

Simon C Shin¹, Divya Thomas¹, Prakash Radhakrishnan², Michael A Hollingsworth³

Affiliations

¹ The Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
² The Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
³ The Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA. Electronic address: mahollin@unmc.edu.

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.

Keywords: Acidic microenvironment; Aerobic glycolysis; EMT; Fatty-acid oxidation; Invasion; Pancreatic cancer.

Abstract

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