Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition

  • Authors:
    • Ines Hartel
    • Michael Ronellenfitsch
    • Christina Wanka
    • Stefan Wolking
    • Joachim P. Steinbach
    • Johannes Rieger
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  • Published online on: April 25, 2016     https://doi.org/10.3892/ijo.2016.3498
  • Pages: 173-180
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Abstract

The epidermal growth factor (EGFR) pathway is frequently activated in glioblastoma but the clinical efficacy of EGFR inhibitors in malignant glioma has been disappointing. The reasons for the failure of the mechanisms of resistance of these inhibitors are unclear, but may involve factors of the tumor microenvironment such as limited glucose availability and hypoxia. It was therefore examined whether glucose and oxygen influenced the response of glioma cells to EGFR inhibition. Decreased levels of glucose and oxygen led to resistance against the EGFR inhibitor PD153035, whereas high glucose amounts and normoxia sensitised glioma cells towards the inhibitor. Low levels of glucose and oxygen stimulated AMP-activated kinase (AMPK) in glioma cells. 2DG, an inhibitor of glycolysis, and the AMPK activator A769662 reduced glucose consumption, induced phosphorylation of AMPK and mimicked the effects of low glucose availability on the toxicity of PD153035. Similarly, 2DG reduced toxicity of imatinib in K562 leukemia cells. In contrast, inhibition of AMPK by compound C or by short-hairpin (sh)-mediated gene suppression increased cell death induced by the EGFR inhibitor and reverted the protective effects of 2DG and A769662. In conclusion, cytotoxicity of EGFR inhibition can be diminished by AMPK activation in glioma cells. These results may provide one explanation for the low activity of EGFR inhibitors in clinical trials and suggest antagonism of AMPK or of AMPK-regulated metabolic alterations as a promising approach to enhance their therapeutic efficacy.
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July-2016
Volume 49 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Hartel I, Ronellenfitsch M, Wanka C, Wolking S, Steinbach JP and Rieger J: Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition. Int J Oncol 49: 173-180, 2016
APA
Hartel, I., Ronellenfitsch, M., Wanka, C., Wolking, S., Steinbach, J.P., & Rieger, J. (2016). Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition. International Journal of Oncology, 49, 173-180. https://doi.org/10.3892/ijo.2016.3498
MLA
Hartel, I., Ronellenfitsch, M., Wanka, C., Wolking, S., Steinbach, J. P., Rieger, J."Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition". International Journal of Oncology 49.1 (2016): 173-180.
Chicago
Hartel, I., Ronellenfitsch, M., Wanka, C., Wolking, S., Steinbach, J. P., Rieger, J."Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition". International Journal of Oncology 49, no. 1 (2016): 173-180. https://doi.org/10.3892/ijo.2016.3498