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Dysregulated pH: a perfect storm for cancer progression

Nature Reviews Cancer volume 11, pages 671–677 (2011)Cite this article

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Abstract

Although cancer is a diverse set of diseases, cancer cells share a number of adaptive hallmarks. Dysregulated pH is emerging as a hallmark of cancer because cancers show a 'reversed' pH gradient with a constitutively increased intracellular pH that is higher than the extracellular pH. This gradient enables cancer progression by promoting proliferation, the evasion of apoptosis, metabolic adaptation, migration and invasion. Several new advances, including an increased understanding of pH sensors, have provided insight into the molecular basis for pH-dependent cell behaviours that are relevant to cancer cell biology. We highlight the central role of pH sensors in cancer cell adaptations and suggest how dysregulated pH could be exploited to develop cancer-specific therapeutics.

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Figure 1: Dysregulated pH creates a perfect storm for cancer progression.
Figure 2: Mechanisms for pH sensing by glycolytic enzymes.
Figure 3: Molecular mechanisms of pH sensors in cell migration and invasion.
Figure 4: Protonation of weakly basic pharmaceuticals reduces cellular uptake.

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Acknowledgements

We thank T. Wittmann, S. Oakes and members of the Barber laboratory for helpful suggestions; K. Van Vliet for sharing data on pH-dependent conformational changes in integrin αvβ3; and C. Smith (University of California, San Francisco, USA) for computations on the pH-dependence of PFK1. Work on the structure and function of actin-binding pH sensors was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship to B.A.W. and a US National Institutes of Health grant, GM58642, to D.L.B.

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Authors and Affiliations

  1. Bradley A. Webb and Diane L. Barber are at the Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, USA.,

    Bradley A. Webb & Diane L. Barber

  2. Michael Chimenti and Matthew P. Jacobson are at the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA.,

    Michael Chimenti & Matthew P. Jacobson

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  1. Bradley A. Webb
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  2. Michael Chimenti
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Correspondence to Diane L. Barber.

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M.P.J. is a consultant to Schrödinger LLC. The other authors declare no competing financial interests.

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Webb, B., Chimenti, M., Jacobson, M. et al. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 11, 671–677 (2011). https://doi.org/10.1038/nrc3110

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