The Role of Sodium Hydrogen Exchanger 1 in Dysregulation of Proton Dynamics and Reprogramming of Cancer Metabolism as a Sequela

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.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…In cancer cells of all types and origins, they manage to keep pHi normal to elevated under all hostile tumor microenvironmental (TME) conditions, like low O 2 , anoxia, a lack of nutrients, low glucose levels and extracellular acidosis, mainly in order to protect themselves from a low pHi that would induce a cancer-selective therapeutic apoptosis. On the one hand, in 2000, Reshkin et al demonstrated that, when the Human Papilloma Virus (HPV) transfected normal cells, the first protein that over-expressed was sodium–hydrogen exchanger 1 (NHE1) [ 36 , 37 ] and the pHi became more alkaline due to such NHE1 over-expression. On the other hand, extracellular signal-regulated kinase (ERK) is one of the proteins that phosphorylates and then activates NHE1 activity.…”

Intracellular pH Regulates Cancer and Stem Cell Behaviors: A Protein Dynamics Perspective

“…Emerging evidence also indicates a critical role for increased pHi in epithelial plasticity, including epithelial to mesenchymal transition (EMT) (8), and stem cell differentiation (9)(10)(11)(12). Moreover, it is now well-established that dysregulated pHi is seen with many diseases, most notably cancers, which often have a constitutively increased pHi (13)(14)(15)(16)(17)(18), and neurodegenerative disorders, which are associated with a constitutively decreased pHi (19,20). Our review focuses on dysregulated pHi dynamics in cancer; however, another feature of cancers is a dysregulated extracellular pH that is lower (∼7.0) compared with normal tissues (∼7.4).…”

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

“…The pH dysregulation observed in cancer cells helps to drive tumor processes, which are highly sensitive to even minimum pHi variations: these are cancer initiation, progression, adaptation, proliferation, migration, and the programming and reprogramming of tumor cell metabolism [14,[123][124][125][126][127]. Furthermore, many effects on biologic processes of a cell are generated as a result of pH-sensitive functions such as the regulation of protein expression, the affinity of proteins to bind with a ligand as well as the activity of ion channels/enzymes [124,128].…”

“…Voltage-gated sodium channels (NaV) Tetrodotoxin (TTX) Sodium-calcium exchanger (Na + /Ca Compound 9t [1,116,123,128,151,152] Na + /K + -ATPase (sodium -potassium adenosine triphosphatase; the Na + /K + pump or sodium-potassium pump)…”