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, Eytan Ruppin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number2997
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

Funding

FundersFunder number
Israeli I-Core
Spanish FPU
University of Maryland Institute for Advanced Computer Studies
University of South Florida School of MedicineR01CA077571
National Cancer InstituteP30CA076292, CA154739
National Institute of Standards and Technology
European Molecular Biology Organization
University of Maryland
Institute for the Promotion of Teaching Science and Technology
European Commission306240
European Research Council614944 SysPharmAD
Ministerio de Economía y CompetitividadBIO2013-44222-R
Israel Science Foundation
Seventh Framework Programme

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