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

ELife
Bree K Grillo-HillDiane L Barber

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 increase proliferation and migration as well as limit 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.

References

Mar 1, 1988·Journal of Cellular Biochemistry·A E LagardeJ M Pouysségur
Aug 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·J PouysségurS Paris
Jul 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·J PouysségurE Van Obberghen-Schilling
Oct 1, 1993·The American Journal of Physiology·R Martinez-ZaguilanR J Gillies
Oct 29, 1996·Proceedings of the National Academy of Sciences of the United States of America·X Lin, D L Barber
Feb 7, 2001·American Journal of Physiology. Cell Physiology·L A McLeanP M Cala
Oct 29, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·S J ReshkinM Tommasino
May 9, 2001·The American Journal of Surgical Pathology·J J Gómez-RománJ F Val-Bernal
May 15, 2001·The Journal of Biological Chemistry·T PangM Shigekawa
Dec 18, 2002·The Journal of Cell Biology·Sheryl P Denker, Diane L Barber
Jun 12, 2003·Methods : a Companion to Methods in Enzymology·Jayanta DebnathJoan S Brugge
Aug 30, 2003·The Journal of Biological Chemistry·Luanna K Putney, Diane L Barber
Feb 6, 2004·American Journal of Physiology. Cell Physiology·Souad R SennouneRaul Martínez-Zaguilán
Feb 26, 2004·Nature Genetics·Annette L ParksHelen L Francis-Lang
Jun 15, 2004·Cell Death and Differentiation·D Lagadic-GossmannV Lecureur
Sep 22, 2005·Nature Reviews. Cancer·Rosa A CardoneStephan J Reshkin
Apr 7, 2007·Cancer Metastasis Reviews·Pawel SwietachAdrian L Harris
May 25, 2007·Nature Reviews. Cancer·Weigang WangJohn Condeelis
Oct 19, 2007·Pflügers Archiv : European journal of physiology·Ana Rosa BeltránGerhard Malnic
Mar 11, 2008·European Journal of Cell Biology·Christian StockStephan J Reshkin
Nov 26, 2008·The Journal of Cell Biology·Christian FrantzDiane L Barber
Nov 27, 2008·The Journal of Clinical Investigation·Pierre SonveauxMark W Dewhirst
May 14, 2009·Pflügers Archiv : European journal of physiology·Christian Stock, Albrecht Schwab
Dec 23, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Katrin DietlMarina P Kreutz
Feb 17, 2010·The Journal of Cell Biology·Mirkka KoivusaloSergio Grinstein
May 11, 2010·Journal of Biomedicine & Biotechnology·Céline PinheiroFátima Baltazar
Jun 16, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Giovanni BuscoStephan J Reshkin
Jul 28, 2010·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Xiaomeng ZhangRobert J Gillies
Jan 26, 2011·Journal of Gastroenterology and Hepatology·Xuekang YangKefeng Dou
Jan 1, 2007·CSH Protocols·Tanya Wolff
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Jul 14, 2011·Neoplasia : an International Journal for Oncology Research·Chaim B ColenSaroj P Mathupala
Aug 13, 2011·Nature Reviews. Cancer·Bradley A WebbDiane L Barber
Jan 24, 2012·Methods in Enzymology·Samantha StehbensTorsten Wittmann

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Citations

Nov 9, 2016·The Journal of Cell Biology·Bryne UlmschneiderTodd G Nystul
Apr 26, 2017·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Stine F PedersenLuis A Pardo
Mar 27, 2018·Acta Physiologica·M FlinckS F Pedersen
Jan 25, 2018·International Journal of Cancer. Journal International Du Cancer·Anne Poder AndersenStine Falsig Pedersen
Feb 17, 2017·Journal of Cell Science·Katharine A WhiteDiane L Barber
Sep 1, 2016·Development·Aurelio A Teleman
Aug 23, 2016·Nature Communications·Ugur EskiocakSean J Morrison
May 18, 2019·Metallomics : Integrated Biometal Science·Martina RaudenskaMichal Masarik
Sep 16, 2017·Nature Reviews. Cancer·Cyril Corbet, Olivier Feron
Aug 2, 2018·Nature Communications·Erez PersiEytan Ruppin
Nov 22, 2017·EMBO Reports·Sumitra TatapudyTodd Nystul
Sep 21, 2019·The Journal of Cell Biology·Enako HosodaKazuyoshi Chiba
Sep 12, 2019·Physiological Reviews·S F Pedersen, L Counillon
Nov 16, 2019·Annual Review of Physiology·Ebbe Boedtkjer, Stine F Pedersen
Feb 15, 2020·PloS One·Avantika Gupta, Hugo Stocker
Feb 13, 2020·International Journal of Molecular Sciences·Salvador HarguindeyJesús Devesa
Oct 14, 2018·The Journal of Cell Biology·Katharine A WhiteDiane L Barber
Apr 18, 2019·The Journal of Biological Chemistry·Rabab A CharafeddineTorsten Wittmann
Apr 11, 2020·Cancers·Holger M Becker, Joachim W Deitmer
Apr 21, 2017·Cold Spring Harbor Symposia on Quantitative Biology·Madeleine J Oudin, Valerie M Weaver
Apr 11, 2020·Cancers·Khalid O AlfaroukStephan J Reshkin
Nov 26, 2020·Molecular Biology of the Cell·Bradley A WebbDiane L Barber
Feb 6, 2021·Archives of Biochemistry and Biophysics·Christopher EinholzErik Schleicher
Mar 5, 2021·Bio-protocol·Enako Hosoda, Kazuyoshi Chiba
Jul 1, 2020·The International Journal of Biochemistry & Cell Biology·Tianyu ZhengBin Liu
Apr 4, 2021·International Journal of Molecular Sciences·Holger M Becker, Joachim W Deitmer
Jul 27, 2021·Cell Cycle·Irina DruzhkovaMarina Shirmanova
Nov 3, 2021·Journal of the American Chemical Society·Caitlin E T DonahueKatharine A White

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Datasets Mentioned

BETA
AF235935

Methods Mentioned

BETA
xenograft
transgenic
PCR
biosensor
flow cytometry
dissection

Software Mentioned

Photoshop
Excel
NIS Elements

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