Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth

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Vinothini Rajeeve1, Wayne Pearce, Marta Cascante

  • 1Analytical Signaling Group, Centre for Cell Signaling, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

The Biochemical Journal
|January 22, 2013
PubMed

Insights

Phosphoinositide 3-kinase (PI3K) pathway activation influences polyamine metabolism. Spermidine promotes cancer cell survival downstream of PI3K/Akt, revealing a feedback loop that sustains tumor growth.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Cancer Research

Background:

  • Phosphoinositide 3-kinase (PI3K) signaling pathways are crucial for numerous cellular functions, including those in cancer.
  • The interplay between PI3K signaling and small molecule metabolism in cancer remains an area of active investigation.

Purpose of the Study:

  • To investigate the role of PI3K in modulating small molecule metabolism, specifically the polyamine pathway.
  • To elucidate the relationship between PI3K/Akt signaling and polyamine metabolites in colorectal cancer.

Main Methods:

  • Utilized liquid chromatography-mass spectrometry (LC-MS) to analyze metabolites in colorectal cancer cell lines with PIK3CA mutations.
  • Employed pharmacological inhibitors targeting PI3K and ornithine decarboxylase (ODC).
  • Assessed tumor growth in a xenograft mouse model.

Main Results:

  • PI3K activation was associated with altered levels of polyamine pathway metabolites, including spermidine.
  • PI3K inhibition decreased polyamine production, while spermidine enhanced cell survival and counteracted PI3K inhibitor effects.
  • Polyamines and PI3K/Akt signaling exhibit reciprocal control, with implications for cancer cell proliferation and survival.

Conclusions:

  • Spermidine mediates cell proliferation and survival downstream of PI3K/Akt signaling.
  • A feedback loop exists where small molecule metabolism regulates kinase signaling, contributing to chronic cancer cell proliferation.
  • Combined inhibition of PI3K and ODC shows synergistic effects on tumor growth, suggesting therapeutic potential.

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