Study of effects of oxidative stress on tumorigensis in LEC rats that shows a high incidence of spontaneous liver cancer.

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We investigated effects of oxidative stress on tumorigensis in LEC rats that shows a high incidence of spontaneous liver cancer.1. Although copper and iron accumulated in the liver of LEC rats in an age-dependent manner, we showed that copper accumulation in the liver of LEC rats induced DNA strand breaks, but accumulation of iron did not.2. The slow repair of potentially lethal damage (PLD) occurred in LEC rat cells but not the fast repair of PLD.Wortmannin, an inhibitor of DNA-dependent protein kinase (DNA-PK) enhances the radiosensitivity of control rat cells but not that of LEC rat cells. Although oxidative stress produces a variety of lesions in DNA, double-strand breaks (DSBs) appear to be responsible for most oxidative stress-induced cell death. Repair of DSBs plays an important role in the fixation of fast-repairing PLD.DNA-PK that is a heterotrimeric complex comprised of two components : a large catalytic subunit (DNA-PKcs) and DNA-targeting component (Ku 70 and Ku 80). In the control cells Ku proteins accumulated in the nucleus after production of DSBs, but did not in LEC rat cells.3. LEC rat cells showed an abnormal accumulation of G2/M-phase cells after treatment with oxidative stress at S phase. LEC rat cells also showed a higher sensitivity to induction of apoptosis after treatment of the cells with a variety of stress.These results suggest that a deficiency of DSBs repair and an abnormality of some signal transduction pathways following oxidative stress may be associated with a high incidence of liver cancer of LEC rats.