Eukaryotic Initiation factor 5B (eIF5B) provides glioblastoma multiforme with resistance towards apoptotic agents
AbstractEukaryotic initiation factors (eIFs) are proteins involved in the general process of mRNA translation. However, under conditions of physiological stress, alternative methods of translation initiation are often activated and relied upon to continue translation of a subset of mRNAs. Specific eIFs such as eIF5B have been shown to use cap-independent mechanisms to promote the production of anti-apoptotic proteins, such as X-linked inhibitor of apoptosis protein (XIAP). In the present study, we have explored if eIF5B provides resistance to glioblastoma multiforme (GBM) cells towards apoptotic agents. Using siRNA, we depleted eIF5B from various GBM cells and treated them with agents that promote apoptosis. In order to activate intrinsic apoptosis pathway we treated these cells with genotoxic agents such as doxorubicin (DXR), and temozolomide (TMZ). Moreover, we treated GBM cells with tumor necrosis factor alpha (TNFα), and/or TNF-related apoptosis-inducing ligand (TRAIL) to activate extrinsic apoptosis pathway. The depletion of eIF5B did not sensitize GBM cells to DXR or TMZ. However, further viability assays showed that knockdown of eIF5B sensitized U343 cells to TRAIL or TRAIL + TNFα. Further, the combination of TRAIL + SMAC- mimetic compounds (SMC) showed statistically significant decreases in cell viability when eIF5B was depleted. So far, six different glioblastoma cell lines have been assessed for this effect, and further studies are underway to observe the effects of eIF5B depletion on cell viability of various cancer and non-cancer cells. Our preliminary data suggest that eIF5B enhances cell survival of GBM cells and could represent a potentially important therapeutic target.
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