PMID- 21985943
OWN - NLM
STAT- MEDLINE
DCOM- 20120319
LR  - 20181201
IS  - 1879-355X (Electronic)
IS  - 0360-3016 (Linking)
VI  - 81
IP  - 5
DP  - 2011 Dec 1
TI  - K-RAS(V12) induces autocrine production of EGFR ligands and mediates 
      radioresistance through EGFR-dependent Akt signaling and activation of DNA-PKcs.
PG  - 1506-14
LID - 10.1016/j.ijrobp.2011.05.057 [doi]
AB  - PURPOSE: It is known that postirradiation survival of tumor cells presenting 
      mutated K-RAS is mediated through autocrine activation of epidermal growth factor 
      receptor (EGFR). In this study the molecular mechanism of radioresistance of 
      cells overexpressing mutated K-RAS(V12) was investigated. METHODS AND MATERIALS: 
      Head-and-neck cancer cells (FaDu) presenting wild-type K-RAS were transfected 
      with empty vector or vector expressing mutated K-RAS(V12). The effect of 
      K-RAS(V12) on autocrine production of EGFR ligands, activation of EGFR downstream 
      pathways, DNA damage repair, and postirradiation survival was analyzed. RESULTS: 
      Conditioned medium collected from K-RAS(V12)-transfected cells enhanced 
      activation of the phosphatidylinositol-3-kinase-Akt pathway and increased 
      postirradiation survival of wild-type K-RAS parental cells when compared with 
      controls. These effects were reversed by amphiregulin (AREG)-neutralizing 
      antibody. In addition, secretion of the EGFR ligands AREG and transforming growth 
      factor alpha was significantly increased upon overexpression of K-RAS(V12). 
      Expression of mutated K-RAS(V12) resulted in an increase in radiation-induced 
      DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation at 
      S2056. This increase was accompanied by increased repair of DNA double-strand 
      breaks. Abrogation of DNA-PKcs phosphorylation by serum depletion or 
      AREG-neutralizing antibody underscored the role of autocrine production of EGFR 
      ligands, namely, AREG, in regulating DNA-PKcs activation in K-RAS mutated cells. 
      CONCLUSIONS: These data indicate that radioresistance of K-RAS mutated tumor 
      cells is at least in part due to constitutive production of EGFR ligands, which 
      mediate enhanced repair of DNA double-strand breaks through the 
      EGFR-phosphatidylinositol-3-kinase-Akt cascade.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Minjgee, Minjmaa
AU  - Minjgee M
AD  - Division of Radiobiology and Molecular Environmental Research, Department of 
      Radiation Oncology, Eberhard Karls University, Tubingen, Germany.
FAU - Toulany, Mahmoud
AU  - Toulany M
FAU - Kehlbach, Rainer
AU  - Kehlbach R
FAU - Giehl, Klaudia
AU  - Giehl K
FAU - Rodemann, H Peter
AU  - Rodemann HP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111008
PL  - United States
TA  - Int J Radiat Oncol Biol Phys
JT  - International journal of radiation oncology, biology, physics
JID - 7603616
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Ligands)
RN  - 0 (Transforming Growth Factor alpha)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Amphiregulin
MH  - Antibodies, Monoclonal/pharmacology
MH  - Cell Line, Tumor
MH  - Cell Survival/physiology
MH  - Culture Media, Conditioned
MH  - DNA Breaks, Double-Stranded
MH  - DNA Repair/*physiology
MH  - DNA-Activated Protein Kinase/*metabolism
MH  - EGF Family of Proteins
MH  - ErbB Receptors/*metabolism
MH  - Genes, ras
MH  - Glycoproteins/immunology/*metabolism
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/immunology/*metabolism
MH  - Ligands
MH  - Mutation
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*physiology
MH  - Radiation Tolerance/*physiology
MH  - Signal Transduction/physiology
MH  - Transfection
MH  - Transforming Growth Factor alpha/*metabolism
EDAT- 2011/10/12 06:00
MHDA- 2012/03/20 06:00
CRDT- 2011/10/12 06:00
PHST- 2011/02/08 00:00 [received]
PHST- 2011/05/06 00:00 [revised]
PHST- 2011/05/31 00:00 [accepted]
PHST- 2011/10/12 06:00 [entrez]
PHST- 2011/10/12 06:00 [pubmed]
PHST- 2012/03/20 06:00 [medline]
AID - S0360-3016(11)02804-5 [pii]
AID - 10.1016/j.ijrobp.2011.05.057 [doi]
PST - ppublish
SO  - Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1506-14. doi: 
      10.1016/j.ijrobp.2011.05.057. Epub 2011 Oct 8.