Decreased expression of DNA repair proteins Ku70 and Mre11 is associated with aging and may contribute to the cellular senescence

The gradual loss of telomeric DNA can contribute to replicative senescence and thus, having longer telomeric DNA is generally considered to provide a longer lifespan. Maintenance and stabilization of telomeric DNA is assisted by binding of multiple DNA-binding proteins, including those involved in double strand break (DSB) repair. We reasoned that declining DSB repair capacity and increased telomere shortening in aged individuals may be associated with decreased expression of DSB repair proteins capable of telomere binding. Our data presented here show that among the DSB repair proteins tested, only the expression of Ku70 and Mre11 showed statistically significant age-dependent changes in human lymphocytes. Furthermore, we found that expressions of Ku70 and Mre11 are statistically correlated, which indicate that the function of Ku70 and Mre11 may be related. All the other DSB repair proteins tested, Sir2, TRF1 and Ku80, did not show any significant differences upon aging. In line with these data, people who live in the regional community (longevity group), which was found to have statistically longer average life span than the rest area, shows higher level of Ku70 expression than those living in the neighboring control community. Taken together, our data show, for the first time, that Ku70 and Mre11 may represent new biomarkers for aging and further suggest that maintenance of higher expression of Ku70 and Mre11 may be responsible for keeping longer life span observed in the longevity group.

The Role of bcl-2 and p53 in Tamoxifen-Induced Apoptosis of Human Breast Cancer Cell Lines / 대한암학회지

PURPOSE: Tamoxifen has been well known as an effective anti-tumor agent against breast cancer. The important role of bcl-2 and p53 proteins in tamoxifen-induced apoptosis of breast cancer cells has been suggested. However, the paradoxical fact that bcl-2 over-expression is assdegrees Ciated with better prognosis in clinic has not yet been clearly explained. To investigate this paradox, we analyzed the effect and dynamics of bcl-2 and p53 on the apoptosis after treatment of breast cancer cells with tamoxifen. MATERIALS AND METHODS: The human breast cancer cell lines MCF-7 and MB MDA-468 were treated with 17-betaestradiol (E2) and tamoxifen. RESULTS: Following tamoxifen treatment, MCF-7 cells underwent apoptosis accompanied by reduced bcl-2 expression. E2 pre-treatment led to the inhibition of tamoxifen-mediated apoptosis and bcl-2 down-regulation. When MB MDA-468 cells were treated with E2 or tamoxifen, bcl-2 and p53 protein expression did not change and apoptosis did not develop. CONCLUSION: We observed that the down-regulation of bcl-2 by tamoxifen treatment can facilitate the apoptosis of breast cancer cells without p53 mutations. This finding was consistent with clinical experiences in which bcl-2 positive tumors were assdegrees Ciated with more indolent phenotypes in breast cancer.

Herpes Simplex virus thymidine kinase gene therapy delivered by retroviral or adenoviral vector in mouse model of lewis lung carcinoma / 결핵

BACKGROUND: The antitumor effects of herpes simplex virus thymidine kinase(HSV-tk) and ganciclovir(GCV) strategies for cancer gene therapy have a the following advantages:1) a direct cytotoxicity to HSV-tk modified cancer cells by GCV 2) a cell death by the local transfer of toxic metabolites from the HSV-tk modified cells to nearby unmodified tumor cells(bystander effect), and 3) in vivo bystander effect such as antitumor-immunity. Retroviral and adenoviral sequences can silence transgene expression in cells and mice. In this study, we investigated the above described advantages of HXV-tk/GCV strategy in Lewis lung cell and mouse lung cancer model using retroviral vector and adenoviral vector. Also, we observed whether the expression of a silenced gene can be reactivated by treating cell with butyrate. METHODS: Retrovirus-HSV-tk and adenovirus-HSV-tk vectors were used for the transduction of Lewis lung carcinoma(LLC) cells. The change of HSV-tk expression by butyrate was measured by Western blot.The antitumor activities containing bystander effect were observed in vivo(by MTT assay) and in vivo tumor models of various combinations of LLC and LLC-tk. RESULTS: 1. Butyrate induced the enhancement of HSV-tk expression from adenovirally transduced cells but not from retrovirally transduced cells. 2. Both retrovirus-HSV-tk and adenovirus-HSV-tk vectors with GCV treatment were effective for killing of tumor cell in vitro and suppression of LLC tumorigenicity. Bystander effect was responsible for killing of mixture of LLC-tk and LLC in vitro and in vivo-tumorigenicity model. CONCLUSION: Butyrate could augment adenoviral vector seems to be an effective approach for lung cancer therapy.