PMID- 14996711
OWN - NLM
STAT- MEDLINE
DCOM- 20040331
LR  - 20201222
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 64
IP  - 5
DP  - 2004 Mar 1
TI  - Inhibition of epidermal growth factor receptor signaling protects human malignant 
      glioma cells from hypoxia-induced cell death.
PG  - 1575-8
AB  - Epidermal growth factor receptor (EGFR) signaling has become an important target 
      for drug development because EGFR signaling enhances tumor cell proliferation, 
      migration, and invasion and inhibits apoptosis. However, the results of clinical 
      trials using EGFR inhibitors in patients with solid tumors have been 
      disappointing. Here, we report a protective effect of the EGFR inhibitors AG1478 
      and PD153035 against cell death induced by acute hypoxia, which contrasts with 
      their proapoptotic effects under normoxia. Under hypoxic conditions, both agents 
      reduced glucose consumption, delayed ATP depletion, and preserved the 
      mitochondrial membrane potential. Exposure either to hypoxia or the EGFR 
      inhibitors under normoxic conditions resulted in the dephosphorylation of 
      ribosomal protein S6, a player in the energy and nutrient-sensing pathway 
      governed by mammalian target-of-rapamycin (mTOR). Combined inhibition of 
      phosphatidylinositol 3'-kinase (PI3K) and extracellular signal-regulated 
      kinase-1/2 (ERK1/2) mimicked the protective effects of EGFR inhibition on 
      hypoxia-induced cell death and protein S6 dephosphorylation. These results 
      caution that therapies targeting EGFR signaling pathways can protect tumor cells 
      from acute hypoxia.
FAU - Steinbach, Joachim P
AU  - Steinbach JP
AD  - Department of Neurology, Hertie Institute for Clinical Brain Research, University 
      of Tubingen, School of Medicine, Tubingen, Germany. 
      joachim.steinbach@uni-tuebingen.de
FAU - Klumpp, Andrea
AU  - Klumpp A
FAU - Wolburg, Hartwig
AU  - Wolburg H
FAU - Weller, Michael
AU  - Weller M
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Tyrphostins)
RN  - 170449-18-0 (RTKI cpd)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Cell Death/drug effects
MH  - *Cell Hypoxia
MH  - DNA Replication/drug effects
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Glioma/drug therapy/*pathology
MH  - Glucose/metabolism
MH  - Humans
MH  - Membrane Potentials/drug effects
MH  - Mitochondria/drug effects/physiology
MH  - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Quinazolines
MH  - Signal Transduction/*drug effects
MH  - Tyrphostins/pharmacology
EDAT- 2004/03/05 05:00
MHDA- 2004/04/01 05:00
CRDT- 2004/03/05 05:00
PHST- 2004/03/05 05:00 [pubmed]
PHST- 2004/04/01 05:00 [medline]
PHST- 2004/03/05 05:00 [entrez]
AID - 10.1158/0008-5472.can-03-3775 [doi]
PST - ppublish
SO  - Cancer Res. 2004 Mar 1;64(5):1575-8. doi: 10.1158/0008-5472.can-03-3775.