Phosphorylation of eIF4E Confers Resistance to Cellular Stress and DNA-Damaging Agents through an Interaction with 4E-T : A Rationale for Novel Therapeutic Approaches
Martínez, Alba (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sesé, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Hernandez-Losa, Javier (Hospital Universitari Vall d'Hebron)
Robichaud, Nathaniel (McGill University)
Sonenberg, Nahum (McGill University)
Aasen, Trond (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2015
Resum:	Phosphorylation of the eukaryotic translation initiation factor eIF4E is associated with malignant progression and poor cancer prognosis. Accordingly, here we have analyzed the association between eIF4E phosphorylation and cellular resistance to oxidative stress, starvation, and DNA-damaging agents in vitro. Using immortalized and cancer cell lines, retroviral expression of a phosphomimetic (S209D) form of eIF4E, but not phospho-dead (S209A) eIF4E or GFP control, significantly increased cellular resistance to stress induced by DNA-damaging agents (cisplatin), starvation (glucose+glutamine withdrawal), and oxidative stress (arsenite). De novo accumulation of eIF4E-containing cytoplasmic bodies colocalizing with the eIF4E-binding protein 4E-T was observed after expression of phosphomimetic S209D, but not S209A or wild-type eIF4E. Increased resistance to cellular stress induced by eIF4E-S209D was lost upon knockdown of endogenous 4E-T or use of an eIF4E-W73A-S209D mutant unable to bind 4E-T. Cancer cells treated with the Mnk1/2 inhibitor CGP57380 to prevent eIF4E phosphorylation and mouse embryonic fibroblasts derived from Mnk1/2 knockout mice were also more sensitive to arsenite and cisplatin treatment. Polysome analysis revealed an 80S peak 2 hours after arsenite treatment in cells overexpressing phosphomimetic eIF4E, indicating translational stalling. Nonetheless, a selective increase was observed in the synthesis of some proteins (cyclin D1, HuR, and Mcl-1). We conclude that phosphorylation of eIF4E confers resistance to various cell stressors and that a direct interaction or regulation of 4E-T by eIF4E is required. Further delineation of this process may identify novel therapeutic avenues for cancer treatment, and these results support the use of modern Mnk1/2 inhibitors in conjunction with standard therapy.
Ajuts:	Ministerio de Ciencia e Innovación PI11/0018 Ministerio de Ciencia e Innovación RD09/0076/00066 Instituto de Salud Carlos III CP10/00624 Instituto de Salud Carlos III PI13/00763
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 10 (april 2015) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0123352
PMID: 25923732

22 p, 4.8 MB

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