Cancer and pH Dynamics: Transcriptional Regulation, Proteostasis, and the Need for New Molecular Tools

SIMPLE SUMMARY: As tumors grow, cancer cells must overcome the normal signals designed to keep cell growth in check. Most cancer cells do this by turning off proteins that prevent growth or turning on proteins that stimulate growth through mutation but also through changes in the levels of these proteins inside cells. This review article summarizes recent research that suggests the acidity or basicity (pH) of the environment inside cancer cells may allow cancer cells to specifically stabilize proteins that help them grow and remove proteins that induce cell death. We also discuss new research tools that allow us to measure and manipulate pH in cells to better understand the role pH plays in enhancing cancer growth and progression. ABSTRACT: An emerging hallmark of cancer cells is dysregulated pH dynamics. Recent work has suggested that dysregulated intracellular pH (pHi) dynamics enable diverse cancer cellular behaviors at the population level, including cell proliferation, cell migration and metastasis, evasion of apoptosis, and metabolic adaptation. However, the molecular mechanisms driving pH-dependent cancer-associated cell behaviors are largely unknown. In this review article, we explore recent literature suggesting pHi dynamics may play a causative role in regulating or reinforcing tumorigenic transcriptional and proteostatic changes at the molecular level, and discuss outcomes on tumorigenesis and tumor heterogeneity. Most of the data we discuss are population-level analyses; lack of single-cell data is driven by a lack of tools to experimentally change pHi with spatiotemporal control. Data is also sparse on how pHi dynamics play out in complex in vivo microenvironments. To address this need, at the end of this review, we cover recent advances for live-cell pHi measurement at single-cell resolution. We also discuss the essential role for tool development in revealing mechanisms by which pHi dynamics drive tumor initiation, progression, and metastasis.