Key contribution of eIF4H-mediated translational control in tumor promotion.
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.
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Charlotte
C
Vaysse
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Céline
C
Philippe
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Yvan
Y
Martineau
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Cathy
C
Quelen
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Corinne
C
Hieblot
Department of Thoracic Surgery, Rangueil-Larrey Hospital, Toulouse, France.
Claire
C
Renaud
Department of Pathology, CHU Rangueil, Toulouse, France.
Yvan
Y
Nicaise
Inserm US006 Crefre, Toulouse, France.
Aurore
A
Desquesnes
San Raffaele Scientific Institute, Milano, Italy.
Maria
M
Pannese
Clinical Trial Office, Cellule Biostatistique Institut Universitaire du Cancer Toulouse, Toulouse, France.
Thomas
T
Filleron
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Department of Pathology, CHU Rangueil, Toulouse, France.
Ghislaine
G
Escourrou
Department of Respiratory Medicine, Broomfield Hospital, Chelmsford, Essex, UK.
Malcolm
M
Lawson
Department of Thoracic Oncology, Papworth Hospital, Cambridge, UK.
Robert C
RC
Rintoul
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Department of Pathology, CHU Rangueil, Toulouse, France.
Marie Bernadette
MB
Delisle
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Stéphane
S
Pyronnet
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.|Department of Pathology, Institut Universitaire du Cancer, Toulouse, France.
Pierre
P
Brousset
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Hervé
H
Prats
INSERM U1037, CRCT, Cancer Research Center of Toulouse, Toulouse, France.|Toulouse University, Paul Sabatier, Toulouse, France.
Christian
C
Touriol
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D014176:Protein Biosynthesis / Q000235:genetics*; D034622:RNA Interference; D000067492:RNAi Therapeutics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; C111495:EIF4H protein, human; D039642:Eukaryotic Initiation Factors; D005047:Etoposide; D002945:Cisplatin
IRES; chemoresistance; eIF4H; helicase; lung carcinoma; translation initiation factor