Abstract
Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.
Highlights
Non-Hodgkin lymphoma (NHL) is the 7th most common cause of cancer in the USA with diffuse large B-cell lymphoma (DLBCL) being the most common type in the US.[1]
In order to determine the association of eIF4E with eIF4G, we repeated this experiment by pulling down eIF4G from the cell lysates of Mantle cell lymphoma cell (MCL) cell lines and demonstrated that the immunoprecipitates of eIF4G fraction in MCL cell lysates were enriched compared to normal B cells and IgG control (Supplemental Figure 1A)
A pull down assay using eIF4E antibody demonstrated that immunoprecipitates of the eIF4E fraction were enriched in malignant B cells, suggesting reciprocal binding between eIF4G and eIF4E in MCL cells (Supplemental Figure 1B)
Summary
Non-Hodgkin lymphoma (NHL) is the 7th most common cause of cancer in the USA with diffuse large B-cell lymphoma (DLBCL) being the most common type in the US.[1]. New treatments are needed that target the specific signal pathways that are activated in lymphoma cells to enhance the initial response and prevent relapse. Recent reviews have described the potential importance of therapies that target protein translation.[2, 3] The translation of mRNA to protein is controlled by the eIF4F complex, a critical regulator of cap-dependent translation in eukaryotes. EIF4E is the cap-binding factor and its overexpression in solid tumor cells is associated with higher rates of cancer recurrence and cancer-related death.[4, 5] Various studies have demonstrated the overexpression of eIF4E in solid malignancies including esophageal cancer [6] and breast cancer;[7] there are currently no available FDAapproved anti-cancer agents that directly target eIF4E The eIF4F complex contains a translation initiation factor 4E (eIF4E), a scaffolding protein eIF4G, and the RNA helicase eIF4A. eIF4E is the cap-binding factor and its overexpression in solid tumor cells is associated with higher rates of cancer recurrence and cancer-related death.[4, 5] Various studies have demonstrated the overexpression of eIF4E in solid malignancies including esophageal cancer [6] and breast cancer;[7] there are currently no available FDAapproved anti-cancer agents that directly target eIF4E
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