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mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer

Amaia Zabala-Letona1,2, Amaia Arruabarrena-Aristorena1, Natalia Martín-Martín1,2

  • 1CIC bioGUNE, Bizkaia Technology Park, 801 building, 48160, Derio, Spain.

Nature
|June 29, 2017
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates polyamine metabolism, crucial for cancer growth. This study reveals mTORC1 controls S-adenosylmethionine decarboxylase 1 (AMD1) stability, impacting cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • The PTEN-PI3K-mTORC1 pathway is critical for cancer cell growth and proliferation.
  • Polyamines are essential metabolites that support oncogenicity.

Purpose of the Study:

  • To investigate the role of mTORC1 in regulating polyamine metabolism in prostate cancer.
  • To identify specific molecular mechanisms linking mTORC1 to polyamine synthesis alterations.

Main Methods:

  • Integrative metabolomics analysis in a mouse model of prostate cancer.
  • Analysis of human prostate cancer biopsies.
  • Assessment of S-adenosylmethionine decarboxylase 1 (AMD1) stability and immunoreactivity.
  • Evaluation of samples from a clinical trial of an mTORC1 inhibitor.

Main Results:

  • mTORC1 regulates polyamine dynamics by controlling the stability of S-adenosylmethionine decarboxylase 1 (AMD1).
  • Tumors exhibit altered production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis.
  • AMD1 is upregulated in human prostate cancer with activated mTORC1.
  • Treatment with an mTORC1 inhibitor (everolimus) decreased AMD1 levels and proliferation.

Conclusions:

  • mTORC1 integrates growth signals to promote an oncogenic metabolic program through polyamine regulation.
  • AMD1 stability is a novel regulatory point controlled by mTORC1, essential for dcSAM production and cancer cell growth.

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