1. Cell Biology
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Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression

  1. Bree K Grillo-Hill
  2. Changhoon Choi
  3. Maite Jimenez-Vidal
  4. Diane L Barber  Is a corresponding author
  1. University of California, San Francisco, United States
Research Article
  • Cited 43
  • Views 2,527
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Cite this article as: eLife 2015;4:e03270 doi: 10.7554/eLife.03270

Abstract

Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increases proliferation and migration as well as limits apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H+ efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive, primary tumor cell lines with inhibiting H+ efflux. Synthetic lethality with reduced H+ efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off-target effects.

Article and author information

Author details

  1. Bree K Grillo-Hill

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Changhoon Choi

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Maite Jimenez-Vidal

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Diane L Barber

    Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, United States
    For correspondence
    diane.barber@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: May 4, 2014
  2. Accepted: March 17, 2015
  3. Accepted Manuscript published: March 20, 2015 (version 1)
  4. Version of Record published: April 13, 2015 (version 2)

Copyright

© 2015, Grillo-Hill et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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