Targeting pH Regulation in Cancer: Combined Mild Alkalosis and NHE1 Inhibition as a Potential Therapy for Clear Cell Renal Cell Carcinoma

Abstract

Acid-base homeostasis is critical for maintaining physiological functions. In cancer, an acidic tumor microenvironment, driven by altered cellular metabolism, plays a pivotal role in tumor progression by fostering aggressive phenotypes, immune evasion, and resistance to therapy, often at the detriment of surrounding normal tissues. The Na⁺/H⁺ exchanger isoform 1 (NHE1) is a key regulator of intracellular pH and a critical factor in cancer cell survival and proliferation. This study aimed to evaluate the effect of mild alkalosis, combined with NHE1 inhibition, on cell viability in normal renal cells and clear cell renal cell carcinoma (ccRCC) cells. Our findings reveal that this therapeutic combination selectively induces cell death in ccRCC cells while sparing normal renal cells. Mechanistically, we demonstrate that NHE1 activity is higher in ccRCC cells than in normal cells. Mild alkalosis enhances NHE1 activity in normal cells but inhibits its activity in cancer cells. Furthermore, prolonged alkaline exposure alters the subcellular localization of NHE1 in the plasma membrane, with distinct patterns observed between normal and cancer cells. These results suggest that targeting NHE1 activity in conjunction with alkalosis represents a promising strategy for ccRCC treatment, providing a potential therapeutic avenue to exploit the differential pH regulation between cancerous and normal cells.