Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma

Oshrat Attar-Schneider, Liat Drucker, Victoria Zismanov, Shelly Tartakover-Matalon, Michael Lishner

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background: Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage. Therefore, eIF4F translation initiation complex components are attractive therapeutic targets. Methods: Protein lysates of myeloma cells (cell lines/patients' bone marrow samples) untreated/treated with bevacizumab were assayed for eIF4GI expression, regulation (NQO1/proteosome dependent fragmentation) (WB, Dicumarol, qPCR) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1. Cells were tested for viability (ELISA), death (FACS) and eIF4GI targets (WB). Results: Previously, we have shown that manipulation of VEGF in myeloma cells attenuated eIF4E dependent translation initiation. Here we assessed the significance of eIF4GI to MM cells. We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon VEGF inhibition attributed to elevated NQO1/proteasome dependent fragmentation and diminished mRNA levels. Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets (SMAD5/ERα/HIF1α/c-Myc). Finally, we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma. Conclusion: Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI, critical to cell phenotype, and mark it as a viable target for pharmacological intervention.

Original languageEnglish
Pages (from-to)1878-1887
Number of pages10
JournalCellular Signalling
Volume26
Issue number9
DOIs
StatePublished - Sep 2014

Funding

FundersFunder number
Roche

    Keywords

    • Bevacizumab
    • EIF4GI
    • Multiple myeloma
    • Translation initiation

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