Translational control in the tumor microenvironment promotes lung metastasis Phosphorylation of eIF4E in neutrophils
The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 10; pp. E2202 - E2209 |
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Main Authors | , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
06.03.2018
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Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Summary: | The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E). We and others have shown that eIF4E availability and phosphorylation promote metastasis in mouse models of breast cancer by selectively augmenting the translation of mRNAs involved in invasion and metastasis. However, the impact of translational control in cell types within the tumor microenvironment (TME) is unknown. Here, we demonstrate that regulatory events affecting translation in cells of the TME impact cancer progression. Mice bearing a mutation in the phosphorylation site of eIF4E (S209A) in cells comprising the TME are resistant to the formation of lung metastases in a syngeneic mammary tumor model. This is associated with reduced survival of prometastatic neutrophils due to decreased expression of the antiapoptotic proteins BCL2 and MCL1. Furthermore, we demonstrate that pharmacological inhibition of eIF4E phosphorylation prevents metastatic progression in vivo, supporting the development of phosphorylation inhibitors for clinical use. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: N.R., B.E.H., and N.S. designed research; N.R., B.E.H., R.I., F.A., J.B., E.H.M., S.V.M., D.L.D., G.L., M.S., Q.G., and S.R.y.C. performed research; N.R., B.E.H., S.V.d.R., W.H.M., M.P., R.G.J., C.A.P., and P.M.S. contributed new reagents/analytic tools; N.R., B.E.H., and S.R.y.C. analyzed data; and N.R. wrote the paper. Contributed by Nahum Sonenberg, January 23, 2018 (sent for review October 5, 2017; reviewed by Nissim Hay and Robert J. Schneider) Reviewers: N.H., University of Illinois at Chicago; and R.J.S., New York University School of Medicine. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1717439115 |