The translational landscape of mTOR signalling steers cancer initiation and metastasis

Nature. 2012 Feb 22;485(7396):55-61. doi: 10.1038/nature10912.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Benzoxazoles / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factors / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Genome / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis* / drug therapy
  • Neoplasm Metastasis* / genetics
  • Phosphoproteins / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Protein Biosynthesis*
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Benzoxazoles
  • EIF4EBP1 protein, human
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • INK128
  • Phosphoproteins
  • Pyrimidines
  • RNA, Messenger
  • Repressor Proteins
  • TOR Serine-Threonine Kinases

Associated data

  • GEO/GSE35469