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.

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

“…Moreover, pathways associated with the UPR and the initiation of protein translation, which is the rate-limiting step in translation, could regulate the acquisition of chemoresistance in TNBC cells [ 9 ]. Recent findings have demonstrated that inhibition of proteins involved in translation initiation, specifically the three members of the eIF4F cap-binding complex eIF4E, eIF4G, and eIF4A, promotes sensitization of tumor cells [ 10 ].…”

Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel

“…With respect to the impact of therepeutic interventions that may be exploited to improve outcomes, the response to RT revealed in this analysis is novel, with clear opposing signal signatures identified between survival groups with differential alterations in RT-specific pathways including UV response UP and DN unfolded protein response (UPR) ( Supplemental Figure 2 ). Previous research has shown that radiosensitization may be mediated by reduced expression of proteins critical to radioresponse ( 59 ), however considering the large number of signals present in Hallmark UV response_DN (144 genes) and UV response _UP (158 genes) and the dynamic nature of the protein signal, conclusions here may be difficult to attribute to any one or even a small set of proteins. UV response_UP was elevated in the intermediate group, and UV response_DN and UPR were decreased in the lowest survival group.…”

Application of Proteomics in the Discovery of Radiosensitive Cancer Biomarkers

“…With the development of precision medicine in clinic practice, there was an urgent need to screen a number of biomarkers for patient’s stratification and thus develop appropriate treatment strategies ( 6 ). Indeed, investigators were dedicated to identify potential radiosensitivity biomarkers to perform tailored radiation therapy for cancer patients ( 7 , 8 ). Big data was the basis for the realization of precision medicine ( 9 ).…”