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

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.DOI: http://dx.doi.org/10.7554/eLife.03270.001

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

“…Importantly, constitutive increases in pH i have been linked to increased migration in cancer cell models (Amith et al, 2015(Amith et al, , 2016aParks and Pouyssegur, 2015;Lin et al, 2012;Cong et al, 2014), and we have recently shown that increased pH i enables cancer cell invasion in an animal model (Grillo-Hill et al, 2015). Importantly, in these studies, decreasing pH i inhibits the migration or invasion phenotype, suggesting that lowering the pH i of cancer cells as part of cancer therapy can limit metastasis.…”

“…Supporting this idea, lowering pH i through genetic knockdown or inhibition of ion transporters reduces cell proliferation and migration Amith et al, 2016a;Le Floch et al, 2011), cell invasion (Yang et al, 2010), and suppresses tumorigenesis in xenograft models (Amith et al, 2015;Lagarde et al, 1988;Sonveaux et al, 2008;Colen et al, 2011;Chiche et al, 2012). Additionally, we have recently shown in Drosophila animal models and human clonal cells that, by lowering the pH i , we can induce synthetic lethality with expression of activated oncogenes -notably Raf and Raspossibly by limiting the efflux of metabolically generated acids (Grillo-Hill et al, 2015). Moreover, increasing pH i in the absence of oncogenes is sufficient to induce hyperproliferation and dysplasia (Grillo-Hill et al, 2015;Petzoldt et al, 2013).…”

“…Subsequent work showed that the pH i -dependent proliferative response in cancer cells can be generated by distinct ion transport proteins, including NHE1 (Lauritzen et al, 2012), Na + -driven bicarbonate transporters (Boedtkjer et al, 2013;McIntyre et al, 2016) and the H + /K + -ATPase proton pump (Goh et al, 2014). Additionally, pH i -dependent proliferation has recently been confirmed in vivo (Grillo-Hill et al, 2015).…”

“…Increased pH i resulting from ion transporter activity has been shown to enable cancer cell migration in oncogene-transformed mammary cells (Lauritzen et al, 2012), in patient-derived glioma cell lines (Cong et al, 2014) and in cervical cancer cell lines that do not exhibit hallmarks of metabolic adaptation (De Saedeleer et al, 2014). Furthermore, increased pH i due to higher ion transporter activity has been linked to cell invasion phenotypes (Lin et al, 2012;Grillo-Hill et al, 2015). For a detailed review of which specific ion transporters have been linked to normal and pathological migration effects, see (Stock and Schwab, 2015).…”

Metabolism meets development at Wiston House

“…As discussed above, Ben Tu's lab showed that the spatial compartmentalization of acetyl-CoA levels in yeast is important for the regulation of histone acetylation (Cai et al, 2011). Diane Barber (University of California, San Francisco, CA, USA) showed that intracellular pH dynamics regulates activity of myriad proteins including metabolic enzymes, as well as cancer cell behaviors including dysplasia in the Drosophila eye (Grillo-Hill et al, 2015). In tumors, it is known that extracellular pH drops, activating metalloproteases, whereas intracellular pH increases.…”