This is a four-year proposal to examine novel anti-tumor activities of ornithine decarboxylase-antizyme (ODC-Az) in carcinogenesis by a DNA demethylation mechanism. ODC-Az is an intracellular inhibitory molecule of ornithine decarboxylase (ODC) enzyme activity that causes polyamine depletion, which is, implicated in anti-proliferation and differentiation. Expression of ODC-Az is, significantly reduced in animal and human oral cancer cells compared with normal counterparts. Forced-expression of the ODC-Az gene in oral cancer cells altered malignant phenotype by re-activation of genes involved in tumor suppression. Several genes up regulated by ODC-Az are known to be silenced in tumor cells owing to aberrant hypermethylation of the promoter region. Based on this evidence, this application proposes experiments to test the following hypotheses; 1) ODC-Az re-activates tumor suppression-related genes silenced in tumor cells by DNA aberrant hypermethylation, 2) ODC-Az is a potential physiological tumor suppressor molecule. This proposal is design to utilize newly developed strategies, such as cDNA arrays, genetically engineered animal of cancer models and protein transduction systems. This is a novel and promising pathway to counter the deregulated growth and differentiation as well as the silencing mechanism of tumor suppressor genes in cancer cells. The mechanism, by which the regulatory genes involved in normal function of growth invasion and metastasis may become affected by DNA methylation, will be, investigated in the proposed studies. There are two Specific Aims in this proposal: 1) To elucidate the gene expression profile regulated by ODC-Az in human head and neck cancer and 2) To validate ODC-Az as a physiological tumor suppressor molecule. The long-term goal of this project is to determine if ODC-Az could be use therapeutically as a physiological growth suppressor, inducer of terminal differentiation, and inducer of DNA demethylation for reactivation of tumor suppressor genes in the treatment of patients with cancer.
|Tsuji, Takanori; Katsurano, Miki; Ibaragi, Soichiro et al. (2007) Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry 46:8920-32|