Ionizing radiation-induced mitogen-activated protein (MAP) kinase activation in DU145 prostate carcinoma cells: MAP kinase inhibition enhances radiation-induced cell killing and G(2)/M-Phase arrest

These studies examine the role(s) played by the mitogen-activated protein k inase (MAPK) pathway after exposure of DU145 prostate carcinoma cells to ra diation. Radiation (2 Gy) was found to cause both immediate primary (0-30 m in) and prolonged secondary activations (90-1440 min) of the MAPK pathway. These activations of the MAPK pathway were abolished by inhibition of epide rmal growth factor receptor (EGFR) function. The secondary activation was a lso abolished by addition of a neutralizing monoclonal antibody against tra nsforming growth factor alpha (TGFA), Activation of the MAPK pathway could be induced in nonirradiated cells by the transfer of medium from irradiated cultures. Neutralizing antibody to TGFA blocked this effect, indicating th at radiation causes secondary activation of the MAPK pathway by release of TGFA in DU145 cells. Radiation induced a transient G(2)/M-phase growth arre st that was prolonged for up to 24 h by inhibition of the MAPK pathway. Inh ibition of the MAPK pathway significantly increased the ability of radiatio n to cause apoptosis 24 h after exposure. The ability of DU145 cells to pro liferate after irradiation became dependent on MAPK signaling, When cells w ere subjected to single doses or fractionated radiation exposure, continuou s inhibition of the MAPK pathway significantly decreased clonogenic surviva l, Only a small fraction of this cell killing could be accounted for by apo ptosis within the first 96 h, Thus inhibition of the MAPK pathway increased radiation-induced cell killing likely by both apoptotic and nonapoptotic m echanisms. Collectively, our findings indicate that disruption of the TGFA/ EGFR/ MAPK pathway may represent a strategy that could be exploited to mani pulate prostate carcinoma growth and cell survival after irradiation. (C) 2 000 by Radiation Research Society.