Eukaryotic Initiation Factor 5B (eIF5B)-Driven Translational Control Impacts Oral Squamous Cell Carcinoma Pathophysiology

Abstract The non-canonical translation of specific mRNAs has been implicated in oncogenesis and cancer progression. We previously identified eukaryotic Initiation Factor 5B (eIF5B) as a key factor in Internal Ribosome Entry Site (IRES)-mediated translation of a subset of mRNAs encoding anti-apoptotic proteins. Here, we demonstrate that EIF5B is predominantly expressed in cancer cells compared to other cell types in the Oral Squamous Cell Carcinoma (OSCC) microenvironment. Higher EIF5B mRNA and protein expression are associated with poor patient outcomes. We show that eIF5B depletion in OSCC cells blunted pro-growth, pro-inflammatory, and pro-angiogenic signaling pathways and significantly increased TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death. This is achieved through decreased translation of mRNAs encoding critical factors associated with OSCC pathophysiology. Importantly, the level of interaction of eIF5B with tRNAi Met was significantly higher in OSCC cells compared to non-cancerous fibroblasts. This suggests that OSCC cells (but not non-cancerous fibroblasts) rely heavily on eIF5B for translation initiation. In an in vivo flank xenograft model using nude mice, eIF5B knockdown in UMSCC-29 cells led to a significant reduction in tumor volume compared to control tumors. Also, the immunohistochemical analysis of the xenografted tumor sections demonstrated decreased staining intensity of critical factors associated with OSCC pathophysiology in eIF5B-depleted tumors relative to controls. Collectively, our data demonstrate that OSCC cells are uniquely dependent on eIF5B–tRNAᵢᴹᵉᵗ interactions to sustain translation of pro-survival mRNAs. Targeting eIF5B disrupts these oncogenic programs, sensitizing OSCC cells to apoptosis and suppressing pro-angiogenic and pro-growth signaling.