Inhibition of Transforming Growth Factor-β Signaling in Normal Lung Epithelial Cells Confers Resistance to Ionizing Radiation

Anna Reeves, Marianna Zagurovskaya, Seema Gupta, Mohammed M. Shareef, Mohammed Mohiuddin, Mansoor M. Ahmed

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Purpose: To address the functional role of radiation-induced transforming growth factor-β (TGF-β) 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-β RII (ΔRII) transgenic mouse that conditionally expressed ΔRII 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-β-responsive promoter activity was measured using dual-luciferase reporter assay. Results: Exposure to ZnSO4 inhibited TGF-β signaling induced either by recombinant TGF-β1 or ionizing radiation. The SILECC, treated with either ZnSO4 or neutralizing antibody against TGF-β, showed a significant increase in radio-resistance compared to untreated cells. Furthermore, the expression of ΔRII inhibited the radiation-induced up-regulation of the TGF-β effector gene p21waf1/cip1. Conclusions: Our findings imply that inhibition of radiation-induced TGF-β 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-β signaling function.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume68
Issue number1
DOIs
StatePublished - May 1 2007

Keywords

  • Ionizing radiation
  • Normal lung cells
  • Radiation resistance
  • TGF-β1 signaling
  • p21

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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