MEK1 and Erk1/2 kinases as targets for the modulation of radiation responses.
BACKGROUND
The activation of mitogenic cascades via Ras, c-Raf-1, MEK-1, Erk1/2 is a hall- mark of oncogenic transformation. The cascade is also anti-apoptotic by modulation of Bcl-2, Bcl-xL and BAD function. The impact of MEK-1 on radiation resistance and the role of drugs targeting MEK-1 for the modulation of resistance is unclear.


METHODS
Activation of MEK-1 in four carcinoma cell lines was analyzed using Erk1/2 phosphospecific antibodies. MEK-1 was blocked by PD98059 (2-amino-3methoxyflavin) and influence on radiation responses was determined by apoptotic morphology, caspase-3 activation and colony formation assays.


RESULTS
MEK-1 kinase was constitutively active and inhibitable by PD98059. The low radiation induced apoptosis rate was not increased by MEK inhibition. PD98059 did not influence cell growth and radiation induced clonogenic cell death.


CONCLUSIONS
Since PD98059 did not alter radiation responses despite blocking MEK-1 kinase, MEK-1 and Erk1/2 are not involved in radiation resistance. Thus PD98059 has no potential in the modulation of radiation responses.
Belka
C
C
Department of Radiotherapy, University of Tuebingen, Germany. claus.belka@uni-tuebingen.de
Knippers
P
P
Rudner
J
J
Faltin
H
H
Bamberg
M
M
Budach
W
W
D017209:Apoptosis / Q000528:radiation effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005419:Flavonoids; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one