5'-cap-dependent translation as a potent therapeutic target for lethal human squamous cell carcinoma.

Abstract Skin squamous cell carcinomas (sSCCs) are a major cause of death in organ transplant patients (OTPs). Moreover, these neoplasms cause significant disease and economic burden and diminish patients’ life quality. However, no effective treatment or intervention strategies are available. Here, we investigated the pathologic role of 5’-cap-translation, which is regulated by the formation of a translation initiation factor complex (TIFC) involving eukaryotic initiation factor 4E (eIF4E), eIF4G, and eIF4A1. We detected increased expression of phosphorylated-eIF4E (p-eIF4E), eIF4G, and eIF4A1 in human and murine sSCCs. The increase in these TIFC proteins was associated with enhanced eIF4E translation targets cyclin D1 and c-Myc. Conversely, siRNA-mediated depletion of eIF4E in human SCC cells (A431 & SCC-13) reduced eIF4G and proteins that regulate the cell cycle and proliferation. Notably, inhibition of Raf/MAPK/ERK signaling decreased eIF4E and p-eIF4E accumulation, significantly diminished cell cycle gene expression and tumor volume of A431-derived xenograft tumors. Furthermore, disrupting the eIF4E with an allosteric inhibitor of eIF4E/eIF4G binding, 4EGI-1, decreased the eIF4E/eIF4G expression and reduced proliferation. Finally, combined inhibition of the Raf/MAPK/ERK axis and eIF4E impaired 5’-cap-dependent translation and abrogated tumor cell proliferation. These data demonstrate that 5’-cap-dependent translation is a potential therapeutic target for abrogating lethal sSCCs in OTPs.