The translational landscape of mTOR signalling steers cancer initiation and metastasis
| Autor: | Nicholas T. Ingolia, Matthew R. Janes, Andrew C. Hsieh, Craig R. Stumpf, Pingda Ren, Carly Christensen, Yi Liu, Kevan M. Shokat, Jonathan S. Weissman, Katti Jessen, Shunyou Wang, Michael Bonham, Christian Rommel, Michael C. Martin, Annie Sher, Evan Y. Shi, Davide Ruggero, Morris E. Feldman, Merritt Edlind |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cell Cycle Proteins Biology Bioinformatics Article Metastasis Mice Prostate cancer Cell Movement Cell Line Tumor medicine Animals Humans Neoplasm Invasiveness RNA Messenger Ribosome profiling Eukaryotic Initiation Factors Neoplasm Metastasis PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Regulation of gene expression Benzoxazoles Genome Multidisciplinary Cell growth TOR Serine-Threonine Kinases RPTOR Prostatic Neoplasms Phosphoproteins medicine.disease Gene Expression Regulation Neoplastic Mice Inbred C57BL Repressor Proteins Eukaryotic Initiation Factor-4E Pyrimidines Protein Biosynthesis Cancer cell Cancer research Signal Transduction |
| Zdroj: | Nature. 485:55-61 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature10912 |
| Popis: | The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the ‘cancerous’ translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted. |
| Databáze: | OpenAIRE |
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