The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Systems analysis of intracellular pH vulnerabilities for cancer therapy
Open accessAbstract
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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Cites
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Self-citationNeutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy
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The multi-factorial nature of clinical multidrug resistance in cancer
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Systems Biology of Cancer Metastasis
Suhail, Y., Cain, M. P., Vanaja, K., Kurywchak, P. A., Levchenko, A., Kalluri, R., & Kshitiz (2019) · Cell Systems · doi:10.1016/j.cels.2019.07.003 · Cited by 452
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Chitosan-Based Nanoparticles of Targeted Drug Delivery System in Breast Cancer Treatment
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Metadata
- Authors
- Persi, E., Duran-Frigola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., & Ruppin, E.
- Venue
- Nature Communications
- Published
- 2018-07-31
- Volume
- 9
- Issue
- 1
- Pages
- 2997-2997
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2883266145
- Cited by
- 406
- References
- 10
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- gold
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