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Key contribution of eIF4H-mediated translational control in tumor promotion.

Published version
Peer-reviewed

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Type

Article

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Authors

Vaysse, Charlotte 
Philippe, Céline 
Martineau, Yvan 
Quelen, Cathy 
Hieblot, Corinne 

Abstract

Dysregulated expression of translation initiation factors has been associated with carcinogenesis, but underlying mechanisms remains to be fully understood. Here we show that eIF4H (eukaryotic translation initiation factor 4H), an activator of the RNA helicase eIF4A, is overexpressed in lung carcinomas and predictive of response to chemotherapy. In lung cancer cells, depletion of eIF4H enhances sensitization to chemotherapy, decreases cell migration and inhibits tumor growth in vivo, in association with reduced translation of mRNA encoding cell-proliferation (c-Myc, cyclin D1) angiogenic (FGF-2) and anti-apoptotic factors (CIAP-1, BCL-xL). Conversely, each isoform of eIF4H acts as an oncogene in NIH3T3 cells by stimulating transformation, invasion, tumor growth and resistance to drug-induced apoptosis together with increased translation of IRES-containing or structured 5'UTR mRNAs. These results demonstrate that eIF4H plays a crucial role in translational control and can promote cellular transformation by preferentially regulating the translation of potent growth and survival factor mRNAs, indicating that eIF4H is a promising new molecular target for cancer therapy.

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Keywords

IRES, chemoresistance, eIF4H, helicase, lung carcinoma, translation initiation factor, Animals, Antineoplastic Agents, Apoptosis, Blotting, Western, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cisplatin, Etoposide, Eukaryotic Initiation Factors, Female, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Lung Neoplasms, Male, Mice, Mice, Nude, NIH 3T3 Cells, Protein Biosynthesis, RNA Interference, RNAi Therapeutics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Burden, Xenograft Model Antitumor Assays

Journal Title

Oncotarget

Conference Name

Journal ISSN

1949-2553
1949-2553

Volume Title

6

Publisher

Impact Journals, LLC