Lipoprotein internalisation induced by oncogenic AMPK activation is essential to maintain glioblastoma cell growth

Eur J Cancer. 2014 Dec;50(18):3187-97. doi: 10.1016/j.ejca.2014.09.014. Epub 2014 Oct 13.

Abstract

Aim of the study: Metabolic adaptations are essential during tumour growth to maintain the high proliferation levels exhibited by cancer cells. In this study, we examined the transformations that occurred in the lipid metabolism in astrocytic tumours, and the possible role of the fuel-sensing enzyme AMPK. Metabolic targets might help design new and effective drugs for cancer.

Methods: To accomplish this objective, we studied both mice and human astrocytic tumours. We first used a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We then confirmed the results in human glioblastoma cell lines and in glioblastoma tissue samples from patients.

Results: We show that the high levels of activated AMPK, observed in astrocytic tumours, increase extracellular lipid internalisation and reduce energy expenditure by inhibiting 'de novo' fatty acid (FA) synthesis, which allows tumour cells to obtain building blocks and energy to be able to create new organelles and new cells.

Conclusions: Our findings demonstrate that AMPK plays a crucial role in glioblastoma cell growth and suggest that blocking lipoprotein receptors could potentially be used as a plausible therapeutic approach for these and other type of tumours with high levels of AMPK.

Keywords: AMPK; Glioma; Lipid metabolism; Lipoprotein receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Astrocytes / enzymology
  • Astrocytes / pathology
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / pathology
  • Cell Proliferation / physiology
  • Fatty Acids / biosynthesis
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Humans
  • Lipid Metabolism / physiology*
  • Mice, Knockout
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • Receptors, Lipoprotein / antagonists & inhibitors
  • Receptors, Lipoprotein / metabolism
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Fatty Acids
  • Receptors, Lipoprotein
  • AMP-Activated Protein Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse