The adenovirus E4ORF6 protein: An inhibitor of DNA double -strand break repair and a radiosensitizer of gliomas.

摘要

Radiation therapy is employed in the treatment of many cancers. As beneficial as radiation therapy is for tumor control, there exists a limit to the dose and frequency with which patients receive radiation, due to the sensitivity of normal tissues. In addition, many tumor cells are able to withstand the damage caused by radiation and continue to proliferate. In the treatment of these radioresistant tumors, such as glioblastoma multiforme, the use of radiosensitizers is of paramount importance. Considering that the cytotoxic effects of radiation exposure are primarily a result of DNA damage, DNA double-strand breaks being the most lethal of lesions; it is not surprising that the inhibition of DNA double-strand break repair results in significant radiosensitization.;We took advantage of evidence that an adenoviral protein, E4orf6, inhibits cellular mechanisms that are dependent on DNA double-strand break repair proteins, and exploited E4orf6 in the radiosensitization of tumor cells. We established that E4orf6 interferes with DNA repair in a manner that results in the significant radiosensitization of both colorectal carcinoma and glioblastoma multiforme cells, in the absence of other adenoviral proteins. We found that E4orf6 does not inhibit re-ligation of broken DNA, but rather acts to prolong the signaling of DNA damage effectively inducing a caspase-independent cell death program.;Our findings identify a role for the interaction between E4orf6 and the cellular repair pathway, independent of adenoviral infection, i.e. other adenoviral proteins, such as E1B-55K. We have provided a new angle for exploration within the adenoviral and DNA repair fields. The use of E4orf6 in this project provides value to the analysis of viral proteins apart from the context of infection. In addition, the cell death program induced by E4orf6 could be a more general, yet unexplored response to the inhibition of DNA double-strand break repair, and warrants further investigation in the realm of DNA repair. Lastly, we have identified a novel and clinically feasible approach of combining viral-vector delivered E4orf6 with ionizing radiation in the treatment of glioblastoma.