Systems analysis of intracellular pH vulnerabilities for cancer therapy

Erez Persi (), Miquel Duran-Frigola, Mehdi Damaghi, William R. Roush, Patrick Aloy, John L. Cleveland, Robert J. Gillies and Eytan Ruppin ()
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Erez Persi: Tel-Aviv University
Miquel Duran-Frigola: The Barcelona Institute of Science and Technology
Mehdi Damaghi: Moffitt Cancer Center and Research Institute
William R. Roush: The Scripps Research Institute
Patrick Aloy: The Barcelona Institute of Science and Technology
John L. Cleveland: Moffitt Cancer Center & Research Institute
Robert J. Gillies: Moffitt Cancer Center and Research Institute
Eytan Ruppin: National Cancer Institute, National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract A reverse pH gradient is a hallmark of cancer metabolism, manifested by extracellular acidosis and intracellular alkalization. While consequences of extracellular acidosis are known, the roles of intracellular alkalization are incompletely understood. By reconstructing and integrating enzymatic pH-dependent activity profiles into cell-specific genome-scale metabolic models, we develop a computational methodology that explores how intracellular pH (pHi) can modulate metabolism. We show that in silico, alkaline pHi maximizes cancer cell proliferation coupled to increased glycolysis and adaptation to hypoxia (i.e., the Warburg effect), whereas acidic pHi disables these adaptations and compromises tumor cell growth. We then systematically identify metabolic targets (GAPDH and GPI) with predicted amplified anti-cancer effects at acidic pHi, forming a novel therapeutic strategy. Experimental testing of this strategy in breast cancer cells reveals that it is particularly effective against aggressive phenotypes. Hence, this study suggests essential roles of pHi in cancer metabolism and provides a conceptual and computational framework for exploring pHi roles in other biomedical domains.

Date: 2018
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DOI: 10.1038/s41467-018-05261-x

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