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Vol. 10, Issue 8, 2493-2506, August 1999
Activates the Epidermal Growth Factor Receptor and
Mitogen-activated Protein Kinase Pathway in Carcinoma Cells, Leading to
Increased Proliferation and Protection from Radiation-induced Cell
Death
Departments of *Radiation Oncology and Exposure of A431 squamous and MDA-MB-231 mammary carcinoma cells to
ionizing radiation has been associated with short transient increases
in epidermal growth factor receptor (EGFR) tyrosine phosphorylation and
activation of the mitogen-activated protein kinase (MAPK) and c-Jun
NH2-terminal kinase (JNK) pathways. Irradiation (2 Gy) of
A431 and MDA-MB-231 cells caused immediate primary activations (0-10
min) of the EGFR and the MAPK and JNK pathways, which were surprisingly
followed by later prolonged secondary activations (90-240 min).
Primary and secondary activation of the EGFR was abolished by molecular
inhibition of EGFR function. The primary and secondary activation of
the MAPK pathway was abolished by molecular inhibition of either EGFR
or Ras function. In contrast, molecular inhibition of EGFR function
abolished the secondary but not the primary activation of the JNK
pathway. Inhibition of tumor necrosis factor Pharmacology
and Toxicology, Massey Cancer Center, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298; and
§Department of Physiology, University of Michigan, Ann
Arbor, Michigan 48109
receptor function by
use of neutralizing monoclonal antibodies blunted primary activation of
the JNK pathway. Addition of a neutralizing monoclonal antibody versus
transforming growth factor (TGF) had no effect on the primary
activation of either the EGFR or the MAPK and JNK pathways after
irradiation but abolished the secondary activation of EGFR, MAPK, and
JNK. Irradiation of cells increased pro-TGF cleavage 120-180 min
after exposure. In agreement with radiation-induced release of a
soluble factor, activation of the EGFR and the MAPK and JNK pathways
could be induced in nonirradiated cells by the transfer of media from irradiated cells 120 min after irradiation. The ability of the transferred media to cause MAPK and JNK activation was blocked when
media were incubated with a neutralizing antibody to TGF. Thus
radiation causes primary and secondary activation of the EGFR and the
MAPK and JNK pathways in autocrine-regulated carcinoma cells. Secondary
activation of the EGFR and the MAPK and JNK pathways is dependent on
radiation-induced cleavage and autocrine action of TGF.
Neutralization of TGF function by an anti-TGF antibody or
inhibition of MAPK function by MEK1/2 inhibitors (PD98059 and U0126) radiosensitized A431 and MDA-MB-231 cells after irradiation in
apoptosis, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), and clonogenic assays. These data demonstrate
that disruption of the TGF-EGFR-MAPK signaling module represents a strategy to decrease carcinoma cell growth and survival after irradiation.
Corresponding author. E-mail
address: PDENT{at}HSC.VCU.EDU.
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