Activation of AMP-activated kinase modulates sensitivity of glioma cells against epidermal growth factor receptor inhibition.
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.
Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, D-60528 Frankfurt, Germany.
Ines
I
Hartel
Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, D-60528 Frankfurt, Germany.
Michael
M
Ronellenfitsch
Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, D-60528 Frankfurt, Germany.
Christina
C
Wanka
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, D-72076 Tübingen, Germany.
Stefan
S
Wolking
Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, D-60528 Frankfurt, Germany.
Joachim P
JP
Steinbach
Dr. Senckenberg Institute of Neurooncology, Goethe University Frankfurt, D-60528 Frankfurt, Germany.
Johannes
J
Rieger
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D020014:K562 Cells; D010766:Phosphorylation; D011753:Pyrones / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D013876:Thiophenes / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D011753:Pyrones; D011799:Quinazolines; D013876:Thiophenes; D000068877:Imatinib Mesylate; C512478:EGFR protein, human; D066246:ErbB Receptors; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline