High salt-induced osmotic stress differentially modulates hepatocellular and renal carcinoma cell proliferation.

Introduction: High salt has been shown to affect cancer cell proliferation, however, its relationship with tumor growth remains controversial and mechanistically unclear. This study aims to elucidate how elevated sodium levels impact cell proliferation in hepatocellular carcinoma (HepG2) and renal carcinoma (Caki-1) cells, particularly under conditions of osmotic stress. Methods: Cells were exposed to high salt (50 mM NaCl above basal medium) and assessed their proliferation and the expression of NFAT5, a crucial osmoprotective transcription factor. The role of NFAT5 was further examined using targeted knockdown or overexpression in both cell lines. Xenograft models were also established using HepG2 or Caki-1 cells in immunocompromised mice, which were fed either a normal-salt (0.3% NaCl chow + tap water) or high-salt (4% NaCl chow + 1% NaCl water) diet. Results: High salt conditions led to a significant reduction in the proliferation of HepG2 cells both Conclusion: Taken together, these findings indicate the potential role of osmotic stress tolerance in the differential effects of hypertonic environments on HepG2 and Caki-1 cell proliferation, highlighting NFAT5 and associated osmoadaptive mechanisms as promising therapeutic targets within the tumor microenvironment.