Aberrant pH Signaling Enhances Cancer Progression: The Link between pH Regulators and Cellular Responses in Cancers
A reversed pH gradient is observed in nearly all types of cancer, demonstrating that aberrant pH signaling is a hallmark of cancers. In order to survive, both cancerous and normal cells require the ability to sense pH changes and respond appropriately to maintain pH homeostasis. Recent work has expanded our knowledge on the molecular basis of pH sensing and regulation in cancers through altered expression or activity of some ion transporters and pH-sensitive proteins (pH sensors). In this review, we will discuss the role of aberrant pH signaling in cancers, with a focus on how dysregulated pH dynamics affect cellular responses, including increased cell proliferation, evasion from apoptosis, metabolic reprogramming, directed cell migration and metastasis. Finally, we assess advances in tools for studying pH dynamics at the single-cell level through the development of FP-based pH biosensors which allow us to visualize intracellular pH in live cells. Increased understanding of the link between pH and cancer cell behaviors brings the potential for cancer therapies via inhibition of ion transporters as well as targeted therapeutics designed to exploit the acidic microenvironment of tumors.