Abstract
To adjust cell growth and proliferation to changing environmental conditions or developmental requirements, cells have evolved a remarkable network of signaling cascades that integrates cues from cellular metabolism, growth factor availability and a large variety of stresses. In these networks, cellular information flow is mostly mediated by posttranslational modifications, most notably phosphorylation, or signaling molecules such as GTPases. Yet, a large body of evidence also implicates cytosolic pH (pHc) as a highly conserved cellular signal driving cell growth and proliferation, suggesting that pH-dependent protonation of specific proteins also regulates cellular signaling. In mammalian cells, pHc is regulated by growth factor derived signals and responds to metabolic cues in response to glucose stimulation. Importantly, high pHc has also been identified as a hall mark of cancer, but mechanisms of pH regulation in cancer are only poorly understood. Here, we discuss potential mechanisms of pH regulation with emphasis on metabolic signals regulating pHc by Na+/H+-exchangers. We hypothesize that elevated NHE activity and pHc in cancer are a direct consequence of the metabolic adaptations in tumor cells including enhanced aerobic glycolysis, generally referred to as the Warburg effect. This hypothesis not only provides an explanation for the growth advantage conferred by a switch to aerobic glycolysis beyond providing precursors for accumulation of biomass, but also suggests that treatments targeting pH regulation as a potential anti-cancer therapy may effectively target the result of altered tumor cell metabolism.
Highlights
To adjust cell growth and proliferation to changing environmental conditions or developmental requirements, cells have evolved a remarkable network of signaling cascades that integrates cues from cellular metabolism, growth factor availability and a large variety of stresses
This hypothesis provides an explanation for the growth advantage conferred by a switch to aerobic glycolysis beyond providing precursors for accumulation of biomass, and suggests that treatments targeting pH regulation as a potential anti-cancer therapy may effectively target the result of altered tumor cell metabolism
While the molecular mechanisms linking glucose or energy metabolism to increased pHc await further clarification, the existing data strongly argue for a tight coupling of glucose metabolism to NHE activity
Summary
We hypothesize that elevated NHE activity and pHc in cancer are a direct consequence of the metabolic adaptations in tumor cells including enhanced aerobic glycolysis, generally referred to as the Warburg effect. Evidence for pH-dependent cell growth is largely based on experiments modulating the activity of Na+/H+-exchangers (NHE) of the SLC9A family of transport proteins These proteins regulate intracellular pH by using the Na+ gradient to transport protons across their target membranes. Increased NHE activity has been linked to multiple aspects of cancer and causes a reversed proton gradient across the plasma-membrane due to elevated pHc, enhanced tumor growth and invasion [3, 35,36,37,38].
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