PMID- 17699110
OWN - NLM
STAT- MEDLINE
DCOM- 20071016
LR  - 20181201
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 5
IP  - 8
DP  - 2007 Aug
TI  - Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR 
      depends indirectly, but not directly, on constitutive K-Ras activity.
PG  - 863-72
AB  - Previous results showed an inducible radiation sensitivity selectively observable 
      for K-RAS-mutated cell lines as a function of epidermal growth factor receptor 
      (EGFR) tyrosine kinase inhibitor blockade of phosphatidylinositol 3-kinase 
      (PI3K)-AKT signaling. Therefore, the role of K-Ras activity for a direct (i.e., 
      through activation of PI3K by K-Ras) or an indirect stimulation of PI3K-AKT 
      signaling (through K-Ras activity-dependent EGFR ligand production) was 
      investigated by means of small interfering RNA and inhibitor approaches as well 
      as ELISA measurements of EGFR ligand production. K-RASmt tumor cells presented a 
      constitutively activated extracellular signal-regulated kinase-1/2 signaling, 
      resulting in enhanced production and secretion of the EGFR ligand amphiregulin 
      (AREG). Medium supernatants conditioned by K-RASmt tumor cells equally 
      efficiently stimulated EGFR signaling into the PI3K-AKT and mitogen-activated 
      protein kinase pathways. Knocking down K-Ras expression by specific small 
      interfering RNA markedly affected autocrine production of AREG, but not PI3K-AKT 
      signaling, after treatment of K-RAS-mutated or wild-type cells with EGFR ligands 
      or exposure to ionizing radiation. These results indicate that PI3K-mediated 
      activation of AKT in K-RASmt human tumor cells as a function of EGFR ligand or 
      radiation stimulus is independent of a direct function of K-Ras enzyme activity 
      but depends on a K-Ras-mediated enhanced production of EGFR ligands (i.e., most 
      likely AREG) through up-regulated extracellular signal-regulated kinase-1/2 
      signaling. The data provide new differential insight into the importance of K-RAS 
      mutation in the context of PI3K-AKT-mediated radioresistance of 
      EGFR-overexpressing or EGFR-mutated tumors.
FAU - Toulany, Mahmoud
AU  - Toulany M
AD  - Division of Radiobiology and Molecular Environmental Research, Department of 
      Radiation Oncology, Eberhard-Karls University Tuebingen, Roentgenweg 11, 72076 
      Tuebingen, Germany.
FAU - Baumann, Michael
AU  - Baumann M
FAU - Rodemann, H Peter
AU  - Rodemann HP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Ligands)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Amphiregulin
MH  - Blotting, Western
MH  - EGF Family of Proteins
MH  - Enzyme-Linked Immunosorbent Assay
MH  - ErbB Receptors/*metabolism
MH  - Fibroblasts/cytology/drug effects/radiation effects
MH  - Genes, ras/*physiology
MH  - Glycoproteins/pharmacology
MH  - Humans
MH  - Immunoprecipitation
MH  - Intercellular Signaling Peptides and Proteins/pharmacology
MH  - Ligands
MH  - Neoplasms/metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation/drug effects/radiation effects
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Small Interfering/pharmacology
MH  - Radiation, Ionizing
MH  - Signal Transduction/drug effects/radiation effects
MH  - Skin/cytology/drug effects/radiation effects
MH  - Tumor Cells, Cultured/radiation effects
EDAT- 2007/08/19 09:00
MHDA- 2007/10/17 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2007/10/17 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - 5/8/863 [pii]
AID - 10.1158/1541-7786.MCR-06-0297 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2007 Aug;5(8):863-72. doi: 10.1158/1541-7786.MCR-06-0297.