Abstract
Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.
Highlights
In most cells, the utilization of glucose by the cell yields energy in the form of ATP and other molecules, ending in CO2 and H+
We shall start out with a general discussion of the dynamics, regulation, and role of intracellular and extracellular pH in cancer processes followed by a discussion of what is known about the interaction of these pH dynamics with the dynamic and regulation of important cellular electrolytes such as sodium, bicarbonate, calcium, potassium, and chloride
In the 1920s, Otto Warburg observed that most cancer cells could perform glycolysis in the presence of oxygen with a dominant production of lactate, which later came to be known as the “Warburg effect” [2,14]
Summary
The utilization of glucose by the cell yields energy in the form of ATP and other molecules, ending in CO2 and H+. During transient low oxygen conditions and in only some relatively adaptable tissues (e.g., skeletal muscle but not in the brain nor heart) glycolysis produces lactate (converted from pyruvate), which is translocated (extruded), via proton-linked monocarboxylate transporters (MCTs), creating an acidic extracellular pHe [2,3,4,5,6,7]. This transient shift in the metabolic program under oxygen scarcity is termed the “Pasteur effect” [8]. We shall start out with a general discussion of the dynamics, regulation, and role of intracellular and extracellular pH in cancer processes followed by a discussion of what is known about the interaction of these pH dynamics with the dynamic and regulation of important cellular electrolytes such as sodium, bicarbonate, calcium, potassium, and chloride
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