Responses to ionizing radiation and translation inhibition in Drosophila melanogaster and human cancer cells.

摘要

A common regimen for the treatment of solid tumors includes ionizing radiation (IR), chemotherapies, and targeted agents, such as kinase inhibitors. Cancer therapies have been traditionally tailored to the tissue origin of the tumor, rather than the mutation type; however, this concept has been changing with evidence that agents targeted to specific mutations are effective in many cancer types. The latter theory assumes that inhibition of the oncogenic mutation trumps differences between tissues, a concept that has never been proven in a whole organism. My results in the first half of this thesis show for the first time that isogenic mutations in separate tissues do in fact respond similarly to treatments in a Drosophila melanogaster tumor model. This indicates that mutation status takes precedence over tissue origin, suggesting that targeted therapies could be used against a specific mutation regardless of cancer type.;Our understanding of oncology has improved drastically over time; however, the identification of new effective agents is still important. Furthermore, understanding the molecular and cellular mechanisms by which these treatments act is essential to effectively combating cancer and identifying patient sub-populations that would benefit from the treatment. My results in the second half of this thesis suggest that bouvardin, a plant-derived molecule with anti-cancer activity, inhibits translation elongation by locking elongation factor 2 (EF2) to the ribosome in human cells. We also found that bouvardin has the ability to enhance the effect of IR in head and neck cancer (HNC) and glioma cells, as well as, mouse xenografts of HNC. The effect of bouvardin and IR treatment on cell growth and proliferation, however, was different between HNC and glioma cells. In HNC cells, bouvardin and IR slows the growth of HNC cells, but does not affect the overall mitotic activity. In glioma cells, the combination treatment inhibits mitotic activity and induces senescence. These results suggest that inhibition of translation elongation is an effective modulator of IR in multiple cancer models.