Ionizing Radiation Causes a Dose-Dependent Release of Transforming Growth Factor αIn vitrofrom Irradiated Xenografts and during Palliative Treatment of Hormone-Refractory Prostate Carcinoma

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Abstract
Purpose: Characterize the radiation response for transforming growth factor (TGF) α shedding in vitro and in vivo. We also report the shedding of TGF α by patients undergoing irradiation for hormone-refractory prostate cancer. Experimental Design: TGF α 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 α. Once released, TGF α 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 α 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 α, and a similar refractory period. Ionizing irradiation also results in the release of TGF α for patients undergoing radiation therapy for hormone-refractory prostate cancer. Conclusions: Irradiation results in a dose-dependent increase in TGF α capable of enhancing the growth of DU145 xenografts. TGF α 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 α release.

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