mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Nature. 2017 Jul 6;547(7661):109-113. doi: 10.1038/nature22964. Epub 2017 Jun 28.

Abstract

Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation is validated in mouse and human cancer specimens. AMD1 is upregulated in human prostate cancer with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibit a predominant decrease in AMD1 immunoreactivity that is associated with a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylmethionine Decarboxylase / immunology
  • Adenosylmethionine Decarboxylase / metabolism*
  • Animals
  • Cell Proliferation
  • Enzyme Activation
  • Everolimus / therapeutic use
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Metabolomics
  • Mice
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polyamines / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Stability
  • S-Adenosylmethionine / analogs & derivatives
  • S-Adenosylmethionine / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Polyamines
  • S-adenosyl-3-methylthiopropylamine
  • S-Adenosylmethionine
  • Everolimus
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • AMD1 protein, human
  • Adenosylmethionine Decarboxylase