Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy

[Image: see text] Introduction: Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. Methods: In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. Results: The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.