Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05261-x
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Funding
- University of Maryland Institute for Advanced Computer Studies (UMIACS)
- Israeli I-CORE Program
- Israeli Science Foundation (ISF)
- EU FP7 INFECT project
- NIST
- IPST
- ERC (SysPharmAD) [614944]
- EU (SyStemAge) [306240]
- MINECO [BIO2013-44222-R]
- NCI [CA154739, R01CA077571]
- NCI Cancer Center Support Grant [P30 CA076292]
- Cortner-Couch Chair for Cancer Research from the University of South Florida School of Medicine
- Terrapin project of UMD
- EMBO
- FEBS
- Spanish FPU
- European Research Council (ERC) [614944] Funding Source: European Research Council (ERC)
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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.
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