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Abstract
Multinucleated cells resulted from mitosis defect have been noted in pathophysiological states of the cells such as inflammation, senescence and cancer. Since oxidative stress has been known to correlate with these pathophysiological conditions, we tested the effect of H2O2 on the cell cycle progression and formation of multinucleated cells. H2O2 induced a significant delay in cell cycle progression in Chang liver cells. Interestingly, H2O2 actively induced hyperamplification of centrosomes (n>or=3) and multipolar spindle formation during mitosis and subsequently increased the generation of multinucleated cells. A significant increase of the phospho-ERK level was observed upon H2O2 treatment but PD98059, an MEK1/2 inhibitor, didn't reduce the frequency of cells with hyperamplified centrosomes. On the other hand, treatment of either H2O2 or adriamycin increased intracellular ROS levels and multinucleated cells, which were significantly suppressed by antioxidants, N-acetylcysteine and PDTC. Thus, our results suggest that oxidative stress can trigger centrosome hyperamplification and multinucleated cell formation, which may promote pathophysiological progression.
Highlights
Centrosomeisanimportantcellularorganelleand playsakeyroleincelldivision.Thecentrosome functionsasamicrotubule-organizingcenter(MTOC), whichcontrolsthepolarityof microtubulesininterphase and generates bipolar mitotic spindles during mitosis(Lange, 2002)
Prolonged oxidative stress has been described as a common causative factor for these diseases
Since H2O2 has been most commonly used inducer for imposing oxidative stress or stressinduced premature senescence, we attempted to investigate whether centrosome abnormalities were involved in increasing genomic instability in cells under oxidative stress
Summary
Centrosomeisanimportantcellularorganelleand playsakeyroleincelldivision.Thecentrosome functionsasamicrotubule-organizingcenter(MTOC), whichcontrolsthepolarityof microtubulesininterphase and generates bipolar mitotic spindles during mitosis(Lange, 2002). Cells were synchronized by the DTB method and H2O2 was added right after removal of 2nd thymidine, followed by 12-24 h incubation. Intracellular ROS levels were determined by using an oxidative-sensitive fluorescence dye, dichlorodihydrofluorescein diacetate (DCF-DA, Molecular Probes) as we previously described (Wang et al, 2003). Multinucleated cells were often described in cells under pathophysiological conditions such as inflammation, senescence and cancer (Devaney et al, 1992, Protzer et al, 1996; Evans 2002; Ren et al, 2005).
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