title: Ionizing radiation-induced mitogen-activated protein (MAP) kinase activation in DU145 prostate carcinoma cells: MAP kinase inhibition enhances radiation-induced cell killing and G2/M-phase arrest.
abstract: These studies examine the role(s) played by the mitogen-activated protein kinase (MAPK) pathway after exposure of DU145 prostate carcinoma cells to radiation. Radiation (2 Gy) was found to cause both immediate primary (0-30 min) and prolonged secondary activations (90-1440 min) of the MAPK pathway. These activations of the MAPK pathway were abolished by inhibition of epidermal growth factor receptor (EGFR) function. The secondary activation was also abolished by addition of a neutralizing monoclonal antibody against transforming 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 that radiation causes secondary activation of the MAPK pathway by release of TGFA in DU145 cells. Radiation induced a transient G(2)/M-phase growth arrest that was prolonged for up to 24 h by inhibition of the MAPK pathway. Inhibition of the MAPK pathway significantly increased the ability of radiation to cause apoptosis 24 h after exposure. The ability of DU145 cells to proliferate after irradiation became dependent on MAPK signaling. When cells were subjected to single doses or fractionated radiation exposure, continuous inhibition of the MAPK pathway significantly decreased clonogenic survival. Only a small fraction of this cell killing could be accounted for by apoptosis within the first 96 h. Thus inhibition of the MAPK pathway increased radiation-induced cell killing likely by both apoptotic and nonapoptotic mechanisms. Collectively, our findings indicate that disruption of the TGFA/EGFR/MAPK pathway may represent a strategy that could be exploited to manipulate prostate carcinoma growth and cell survival after irradiation.
authors.affiliation: Departments of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hagan
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J R
authors.initials: JR
authors.lastname: Hanley
authors.forename: J S
authors.initials: JS
authors.lastname: Park
authors.forename: P
authors.initials: P
authors.lastname: Dent
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D016195:G2 Phase; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008938:Mitosis; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D011839:Radiation, Ionizing; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D016203:CDC2 Protein Kinase; D020928:Mitogen-Activated Protein Kinases