Article

Dysregulated pH: A perfect storm for cancer progression

Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, USA.
Nature Reviews Cancer (Impact Factor: 29.54). 08/2011; 11(9):671-7. DOI: 10.1038/nrc3110
Source: PubMed

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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    • "However, many cancers have elevated expression or activity of proteins that facilitate increased pHi, including carbonic anhydrase 9 (Swietach et al., 2007), H + -ATPases (Martinez-Zaguilan et al., 1993; Sennoune et al., 2004; Hinton et al., 2009), the ubiquitously expressed Na + -H + exchanger NHE1 (McLean et al., 2000; Miraglia et al., 2005; Chiang et al., 2008; Yang et al., 2011) and the monocarboxylate transporter family members MCT1 and MCT4 (Pinheiro et al., 2010; Halestrap, 2013). Therapeutic targeting of these proteins to reduce H + efflux and lower pHi has been suggested for limiting cancer progression (Webb et al., 2011; Harguindey et al., 2013), based primarily on findings with xenograft models and isolated cells. Xenograft tumor growth is suppressed by inhibiting NHE1 (Lagarde et al., 1988; Yang et al., 2011) or MCT1 (Sonveaux et al., 2008; Colen et al., 2011) activity. "
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