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Methotrexate elicits pro-respiratory and anti-growth effects by promoting AMPK signaling

David J Papadopoli1,2, Eric H Ma2,3,4, Dominic Roy2

  • 1Department of Biochemistry, McGill University, Montréal, QC, H3G 1Y6, Canada.

Scientific Reports
|May 14, 2020
PubMed

Insights

Methotrexate impacts cancer cell metabolism by activating AMPK, reducing proliferation, and boosting energy production. This metabolic shift is crucial for its anti-cancer effects and response.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Metabolic Pathways

Background:

  • One-carbon metabolism is essential for cancer cell proliferation, supplying building blocks for nucleotides.
  • Current cancer therapies targeting this pathway have unclear global metabolic impacts.
  • Understanding methotrexate's effects on cellular metabolism is critical for optimizing cancer treatment.

Purpose of the Study:

  • To investigate the global metabolic effects of methotrexate on cancer cells.
  • To elucidate the role of AMP-activated protein kinase (AMPK) in mediating methotrexate's actions.
  • To explore potential therapeutic combinations involving methotrexate and AMPK activators.

Main Methods:

  • Utilized real-time bioenergetics assays to measure cellular energy production.
  • Employed metabolomics to analyze global changes in cellular metabolites.
  • Investigated the impact of methotrexate on gene expression and cellular proliferation.
  • Assessed the role of AMPK by comparing methotrexate effects in cells with varying AMPK activity.

Main Results:

  • Methotrexate treatment elevated intracellular AICAR, leading to AMPK activation.
  • AMPK activation by methotrexate decreased one-carbon metabolism gene expression and proliferation.
  • Methotrexate treatment enhanced global bioenergetic capacity in cancer cells.
  • The anti-proliferative and pro-respiratory effects of methotrexate were dependent on AMPK activity.
  • Combining methotrexate with phenformin (an AMPK activator) potentiated anti-proliferative effects.

Conclusions:

  • Methotrexate exerts reciprocal effects on anabolic and catabolic processes in cancer cells.
  • AMPK activation is a key metabolic determinant of methotrexate's anti-cancer efficacy.
  • Targeting AMPK in conjunction with methotrexate may enhance cancer therapy outcomes.

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