Ionizing radiation causes a dose-dependent release of transforming growth factor alpha in vitro from irradiated xenografts and during palliative treatment of hormone-refractory prostate carcinoma.
OBJECTIVE
Characterize the radiation response for transforming growth factor (TGF) alpha shedding in vitro and in vivo. We also report the shedding of TGF alpha by patients undergoing irradiation for hormone-refractory prostate cancer.


METHODS
TGF alpha levels were determined by ELISA. DU145 xenografts were established on the flanks of athymic nu/nu mice. Expression of phospho-extracellular signal-regulated kinase (ERK)1/2 and phospho-epidermal growth factor receptor (EGFR) and the DNA repair proteins XRCC1 and ERCC1 were determined by Western analyses.


RESULTS
Exposure to ionizing radiation results in a dose-dependent release of TGF alpha. Once released, TGF alpha stimulates EGFR-ERK1/2 signaling in unirradiated cells. Blockade of the EGFR with the tyrphostin AG1478 eliminates the up-regulation XRCC1 and ERCC1 by TGF alpha or irradiation. After irradiation, cells are refractory to additional transactivation of EGFR by additional irradiation for 8 to 12 hours. Irradiation during this refractory period does not increase the expression of XRCC1 or ERCC1. Ligand activation of EGFR is maintained during the refractory period. Irradiation of DU145 xenografts also results in the activation of ERK1/2, release of TGF alpha, and a similar refractory period. Ionizing irradiation also results in the release of TGF alpha for patients undergoing radiation therapy for hormone-refractory prostate cancer.


CONCLUSIONS
Irradiation results in a dose-dependent increase in TGF alpha capable of enhancing the growth of DU145 xenografts. TGF alpha is also shed following radiation therapy of patients treated for hormone-refractory prostate cancer. Radiation transactivation of the EGFR produces a radio-refractory period, which lasts for several hours. During this period, additional irradiation fails to induce XRCC1, ERCC1, or additional TGF alpha release.
Hagan
Michael
M
Department of Radiation, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA. mphagan@hsc.vcu.edu
Yacoub
Adly
A
Dent
Paul
P
D000230:Adenocarcinoma / Q000378:metabolism / Q000532:radiotherapy*; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D004720:Endonucleases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000532:radiotherapy*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D011839:Radiation, Ionizing; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014916:Whole-Body Irradiation; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D016211:Transforming Growth Factor alpha; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse