Abstract
Cancer cells have an unusual regulation of hydrogen ion dynamics that are driven by poor vascularity perfusion, regional hypoxia, and increased glycolysis. All these forces synergize/orchestrate together to create extracellular acidity and intracellular alkalinity. Precisely, they lead to extracellular pH (pHe) values as low as 6.2 and intracellular pH values as high as 8. This unique pH gradient (∆pHi to ∆pHe) across the cell membrane increases as the tumor progresses, and is markedly displaced from the electrochemical equilibrium of protons. These unusual pH dynamics influence cancer cell biology, including proliferation, metastasis, and metabolic adaptation. Warburg metabolism with increased glycolysis, even in the presence of Oxygen with the subsequent reduction in Krebs’ cycle, is a common feature of most cancers. This metabolic reprogramming confers evolutionary advantages to cancer cells by enhancing their resistance to hypoxia, to chemotherapy or radiotherapy, allowing rapid production of biological building blocks that support cellular proliferation, and shielding against damaging mitochondrial free radicals. In this article, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression, adaptation, and in determining the programming and re-programming of tumor cell metabolism.
Highlights
Malignant transformation of a normal cell is the first step in the evolutionary arc of cancer [1]
The many suggested mechanisms to explain the metabolic transformation resulting in the Warburg effect include: (i) Adaptation to transient hypoxia; (ii) Insulin resistance; (iii) Abnormal enzyme content, alteration of enzymatic, and isozymatic activities; (iv) Problems of compartmental transport translocation of pyruvate to the mitochondria; (v) Abnormal content of mitochondria, as well as decreasing the mitochondrial number, and changing the quality of mitochondria; (vi) Abnormal electron transport and decreasing ATP production; and (vii) Oncogenes and suppressor genes [1,4,5]
Experiments observed that ras and v-mos oncogene-dependent transformation results in a rapid cytoplasmic alkalinization, which was implicated as a crucial factor in neoplastic transformation driven by these oncogenes [19,20]. These studies observed that these oncogene-dependent neoplastic transformations resulted in increased NHE1 activity and glycolysis, but it was not clear at the time if the driving factor for elevated pHi was the stimulated NHE1 or the increased glycolysis. This question was resolved in a study utilizing an oncogene (HPV16 E7) in an inducible vector to determine the time course of the appearance of the tumor’s hallmark characteristics, which showed that the activation of the NHE1 with the subsequent cytosolic alkalinization is the initial step in the oncogene-driven transformation of normal cells, which drove the subsequent development of a series of cancer hallmarks such as glycolysis in aerobic conditions (e.g., Warburg metabolism), increased growth rate, substrate-independent growth, growth factor independence, and tumor growth in nude mice [8,21]
Summary
Malignant transformation of a normal cell is the first step in the evolutionary arc of cancer [1]. This work presents the current understanding of the role of pH and the NHE1 in driving transformation and determining the appearance of other ‘hallmark’ cancer characteristics [8] Both ion transport and cytoplasmic pH play critical roles in many cell functions, including management of cell growth and proliferation, growth factor kinetics, cell membrane potential, mitochondrial activity, cell volume, enzyme activity, nucleic acid, differentiation, oncogenesis, and oncogene action [9,10,11,12,13,14,15]. The prevailing hypothesis most often considers the formation of the reversed pH gradient to be a characteristic of advanced, hypoxic tumors where the classical hypoxia-induced glycolytic metabolism is turned on This creates high intracellular lactate and proton levels, with a consequent up-regulation of proton and lactate extruders to compensate the cytosolic acidity, such that the cytosol becomes alkalinized [18]. Sci. 2019, 20, 3694 the earliest steps of malignant transformation and is tightly associated with the first observance of glycolysis in the oxygenated environment (termed the Warburg effect)
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