Translation initiation machinery as a tumor selective target for radiosensitization

Abstract

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.