Understanding and Targeting the Eukaryotic Translation Initiation Factor eIF4E in Head and Neck Cancer

Abstract

The eukaryotic translation initiation factor eIF4E is elevated in about 30% of human malignancies including HNSCC where its levels correlate with poor prognosis. Here, we discuss the biochemical and molecular underpinnings of the oncogenic potential of eIF4E. Studies in human leukemia specimens, and later in a mouse model of prostate cancer, strongly suggest that cells with elevated eIF4E develop an oncogene dependency to it, making them more sensitive to targeting eIF4E than normal cells. We describe several strategies that have been suggested for eIF4E targeting in the clinic: the use of a small molecule antagonist of eIF4E (ribavirin), siRNA or antisense oligonucleotide strategies, suicide gene therapy, and the use of a tissue-targeting 4EBP fusion peptide. The first clinical trial targeting eIF4E indicates that ribavirin effectively targets eIF4E in poor prognosis leukemia patients and more importantly leads to striking clinical responses including complete and partial remissions. Finally, we discuss the relevance of these findings to HNSCC.

Figure 1

FaDu cells immunostained for eIF4E showing cytoplasmic and nuclear localization. Cells were stained using eIF4E mAb conjugated directly to FITC (green) and nuclear marker DAPI (blue) as described [37, 47]. Micrographs were collected on laser scanning confocal microscope using 100X objective and 2x digital zoom.

Figure 2

A diagram summarizing the nuclear and cytoplasmic functions of eIF4E. Some factors that directly regulate eIF4E functions and proteins involved in regulation of eIF4E subcellular distribution are shown. Not all regulators are shown for the sake of clarity. mRNAs are depicted as black lines with black balls denoting the 5′m⁷cap and with/without complex 5′UTRs shown in red and 4ESE element shown in green.