Differential susceptibility of nonmalignant human breast epithelial cells and breast cancer cells to thiol antioxidant-induced G(1)-delay.
Reactive oxygen species (ROS) and ROS signaling have been implicated in a variety of human pathophysiological conditions that involve aberrant cellular proliferation, particularly cancer. We hypothesize that intracellular redox state differentially affects cell-cycle progression in nonmalignant versus malignant cells. The thiol antioxidant, N-acetyl-L-cysteine (NAC), was used to alter intracellular redox state in nonmalignant human breast epithelial (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB-231). Treatment of cells with NAC resulted in significant augmentation of intracellular small-molecular-weight thiols, glutathione and cysteine. In addition, NAC treatment decreased oxidation of a prooxidant-sensitive dye in MCF-10A cells, but not in MDA-MB-231 and MCF-7 cells. NAC-induced shifts in intracellular redox state toward a more reducing environment caused G(1) delays in MCF-10A cells without causing any significant changes in MCF-7 and MDA-MB-231 cell-cycle progression. NAC treatment of MCF-10A (but not MCF-7 and MDA-MB-231) was accompanied by a decrease in cyclin D1 and an increase in p27 protein levels, which correlated with increased retinoblastoma protein hypophosphorylation. These results show differential redox control of progression from G(1) to S in nonmalignant versus malignant cells and support the hypothesis that loss of a redox control of the cell cycle could contribute to aberrant proliferation seen in cancer cells.
Menon
Sarita G
SG
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
Coleman
Mitchell C
MC
Walsh
Susan A
SA
Spitz
Douglas R
DR
Goswami
Prabhat C
PC
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001940:Breast / Q000166:cytology* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000975:Antioxidants; D018797:Cell Cycle Proteins; D013438:Sulfhydryl Compounds; D000111:Acetylcysteine