Lipid peroxide-induced redox imbalance differentially mediates CaCo-2 cell proliferation and growth arrest

Abstract

Dietary oxidants like lipid hydroperoxides (LOOH) can perturb cellular glutathione/glutathione disulphide (GSH/GSSG) status and disrupt mucosal turnover. This study examines the effect of LOOH on GSH/GSSG balance and phase transitions in the human colon cancer CaCo‐2 cell. LOOH at 1 or 5 µm were noncytotoxic, but disrupted cellular GSH/GSSG and stimulated proliferative activity at 6 h that paralleled increases in ornithine decarboxylase activity, thymidine incorporation, expression of cyclin D1/cyclin‐dependent kinase 4, phosphorylation of retinoblastoma protein, and cell progression from G₀/G₁ to S. At 24 h, LOOH‐induced sustained GSH/GSSG imbalance mediated growth arrest at G₀/G₁ that correlated with suppression of proliferative activity and enhanced oxidative DNA damage. LOOH‐induced cell transitions were effectively blocked by N‐acetylcysteine. Collectively, the study shows that subtoxic LOOH levels induce CaCo‐2 GSH/GSSG imbalance that elicits time‐dependent cell proliferation followed by growth arrest. These results provide insights into the mechanism of hydroperoxide‐induced disruption of mucosal turnover with implications for understanding oxidant‐mediated genesis of gut pathology.