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The translational landscape of mTOR signalling steers cancer initiation and metastasis

Andrew C Hsieh1, Yi Liu, Merritt P Edlind

  • 1School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.

Nature
|February 28, 2012
PubMed

Insights

Oncogenic mTOR signaling drives specialized translation of prostate cancer genes, promoting metastasis. A novel mTOR inhibitor, INK128, effectively reprograms this signature, offering therapeutic potential for incurable prostate cancer metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Translational Medicine

Background:

  • The mammalian target of rapamycin (mTOR) kinase regulates protein synthesis, cell growth, and cancer.
  • Downstream translational control of gene expression in cancer development is not well understood.

Purpose of the Study:

  • To investigate the role of oncogenic mTOR signaling in prostate cancer gene expression and metastasis.
  • To identify translationally regulated genes and messenger RNAs (mRNAs) driving prostate cancer invasion.
  • To evaluate the therapeutic potential of an mTOR inhibitor against prostate cancer metastasis.

Main Methods:

  • Ribosome profiling to analyze gene translation in prostate cancer.
  • Functional characterization of pro-invasion mRNAs.
  • Development and testing of an ATP site inhibitor of mTOR (INK128).

Main Results:

  • Oncogenic mTOR signaling directs specialized translation of prostate cancer genes involved in proliferation, metabolism, and invasion.
  • A specific class of translationally controlled pro-invasion mRNAs drives prostate cancer invasion and metastasis downstream of mTOR.
  • INK128 effectively reprograms this gene expression signature and shows therapeutic benefit in preclinical models of prostate cancer metastasis.

Conclusions:

  • The study elucidates how the 'cancerous' translation machinery, regulated by mTOR, drives specific cancer behaviors like metastasis.
  • Targeting this translation machinery with inhibitors like INK128 represents a promising therapeutic strategy for prostate cancer metastasis.

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