Inhibition of Transforming Growth Factor-{beta} Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation
- Weis Center for Research, Geisinger Clinic, Danville, PA (United States)
- Geisinger-Fox Chase Cancer Center, Geisinger Clinic, Wilkes-Barre, PA (United States)
- Weis Center for Research, Geisinger Clinic, Danville, PA (United States) and Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA (United States)
Purpose: To address the functional role of radiation-induced transforming growth factor-{beta} (TGF-{beta}) signaling in a normal epithelial background, we selected a spontaneously immortalized lung epithelial cell line derived from the normal lung tissue of a dominant-negative mutant of the TGF-{beta} RII ({delta}RII) transgenic mouse that conditionally expressed {delta}RII under the control of the metallothionein promoter (MT-1), and assessed this cell line's response to radiation. Methods and Materials: A spontaneously immortalized lung epithelial cell culture (SILECC) was established and all analyses were performed within 50 passages. Colony-forming and terminal transferase dUPT nick end labeling (TUNEL) assays were used to assess clonogenic inhibition and apoptosis, respectively. Western-blot analysis was performed to assess the kinetics of p21, bax, and RII proteins. Transforming growth factor-{beta}-responsive promoter activity was measured using dual-luciferase reporter assay. Results: Exposure to ZnSO{sub 4} inhibited TGF-{beta} signaling induced either by recombinant TGF-{beta}1 or ionizing radiation. The SILECC, treated with either ZnSO{sub 4} or neutralizing antibody against TGF-{beta}, showed a significant increase in radio-resistance compared to untreated cells. Furthermore, the expression of {delta}RII inhibited the radiation-induced up-regulation of the TGF-{beta} effector gene p21{sup waf1/cip1}. Conclusions: Our findings imply that inhibition of radiation-induced TGF-{beta} signaling via abrogation of the RII function enhances the radio-resistance of normal lung epithelial cells, and this can be directly attributed to the loss of TGF-{beta} signaling function.
- OSTI ID:
- 20951632
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 68, Issue 1; Other Information: DOI: 10.1016/j.ijrobp.2006.12.057; PII: S0360-3016(07)00083-1; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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