Lipid peroxide-induced redox imbalance differentially mediates CaCo-2 cell proliferation and growth arrest.
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 micro m 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.
Gotoh
Yudai
Y
Department of Molecular and Cellular Physiology, Loisiana State University Medical Center, Shreveport, LA 71130, USA.
Noda
Takahiro
T
Iwakiri
Ryuichi
R
Fujimoto
Kazuma
K
Rhoads
Carol A
CA
Aw
Tak Yee
TY
D000111:Acetylcysteine / Q000494:pharmacology; D015415:Biomarkers; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D020895:Enterocytes / Q000166:cytology* / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D008054:Lipid Peroxides / Q000494:pharmacology; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium
D015415:Biomarkers; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D014316:Tritium; D005978:Glutathione; D019803:Glutathione Disulfide; D013936:Thymidine; D000111:Acetylcysteine