Abstract
eIF4E is the key regulator of protein translation and critical for translation. The oncogenic potential of tumorigenesis, which is highly contingent on cap-dependent eIF4E, also arises from the critical role in the nuclear export and cytosolic translation of oncogenic transcripts. Inhibition of Exportin1 (XPO1), which is the major nuclear export protein for eIF4E-bound oncoprotein mRNAs, results in decreased tumor cell growth in vitro and in vivo, suggesting that eIF4E is critical in multiple myeloma. Indeed, we found that eIF4E is overexpressed in myeloma cell lines and primary myeloma cells compared with normal plasma cells. Although stable overexpression of eIF4E in multiple myeloma cells significantly increases tumorigenesis, knockdown of eIF4E impairs multiple myeloma tumor progression in a human xenograft mouse model. Using a tet-on-inducible eIF4E-knockdown system, eIF4E downregulation blocks multiple myeloma tumor growth in vivo, correlating with decreased eIF4E expression. Further overexpression and knockdown of eIF4E revealed that eIF4E regulates translation of mRNAs with highly complex 5'-untranslated regions, such as c-MYC and C/EBPβ, and subsequently proliferation in multiple myeloma cells, but not in nonmalignant bone marrow stromal cells. Because many transcription factors that are critical for multiple myeloma proliferation exhibit a higher dependency on protein translation, eIF4E is an ideal and selective tool to target multiple myeloma cell growth. Mol Cancer Ther; 15(4); 711-9. ©2016 AACR.
Highlights
EIF4E plays a central role in protein synthesis and has a key role in the control of cell growth, proliferation, differentiation, and metabolism in eukaryotic cells [1]
It is known that the expressions of proteins, such as c-MYC, Cyclin D1, CCAAT/ enhancer-binding protein beta (C/EBPb), and VEGF, are regulated at the translational level by eIF4E [3,4,5,6]
Because these factors are critically involved in www.aacrjournals.org multiple myeloma cell growth and survival, eIF4E might be an attractive target for antimyeloma treatment [17]
Summary
EIF4E plays a central role in protein synthesis and has a key role in the control of cell growth, proliferation, differentiation, and metabolism in eukaryotic cells [1]. It recognizes and binds to the 7methylguanosine cap in the 50 untranslated regions (50UTR) of mRNAs, transporting these mRNAs to the eIF4F translation initiation complex, which includes eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. An increase in eIF4E level or activity does not lead to increased rates of global translation, but instead results in increased translation of mRNAs with highly complex 50UTRs [2]. Several genes, including MYC, Cyclin D1, CCAAT/ enhancer-binding protein beta (C/EBPb), and VEGF, involved in tumorigenesis are regulated at the translational level by eIF4E [3,4,5,6]. EIF4E competitive inhibitors, such as Exportin (XPO1) inhibitors, abrogate its prosurvival function by decreasing export and translation of target mRNAs [7]. In acute myeloid leukemia (AML), the XPO1 inhibitor KPT-330 (Karyopharm Therapeutics) induced decreased levels of proteins derived from capped
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