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Unlike Esophageal Squamous Cells, Barrett's Epithelial Cells Resist Apoptosis by Activating the Nuclear Factor-B Pathway

¹ Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical School and ² the Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and ³ Department of Medicine, Vanderbilt University, Nashville, Tenessee

Requests for reprints: Rhonda F. Souza, Department of GI, MC# 111B1, Dallas VA Medical Center, 4500 South Lancaster Road, Dallas, TX 75216. Phone: 214-857-0301; Fax: 214-857-0328; E-mail: rhonda.souza{at}utsouthwestern.edu.

Key Words: Barrett's esophagus • esophageal squamous cell • DNA damage • apoptosis • NF-B • Bcl-2

Apoptosis is an important mechanism for maintaining tissue homeostasis and for preventing the proliferation of cells with mutations that could result in malignancy. Barrett's epithelium has been reported to be more resistant to apoptosis than normal esophageal squamous epithelium. We have explored the contribution of the nuclear factor-B (NF-B) pathway to apoptotic resistance in non-neoplastic, telomerase-immortalized esophageal squamous (NES) and Barrett's (BAR-T) epithelial cell lines. We exposed these cells to UV-B irradiation in doses known to cause DNA damage and to induce apoptosis in normal cells, and studied apoptosis as well as the expression of phospho-H2AX, NF-B, Bcl-2, XIAP, cIAP-1, and survivin proteins. We also used Bay 11-7085 and siRNAs to NF-B and Bcl-2 to assess the effects of NF-B and Bcl2 inhibition on apoptosis. UV-B irradiation at low doses (50 and 100 J/m²) caused DNA damage in both NES and BAR-T cells but significantly increased apoptosis only in NES cells. UV-B irradiation caused a decrease in the levels of NF-B, Bcl-2, cIAP-1, XIAP, and survivin in NES cells but increased the levels of those proteins in BAR-T cells. The resistance of BAR-T cells to apoptosis induced by low-dose UV-B irradiation was abolished by Bay 11-7085 and by siRNA for NF-B and was decreased significantly by siRNA for Bcl-2. We conclude that the ability of Barrett's epithelial cells to activate the NF-B pathway when they have sustained DNA damage allows them to resist apoptosis. This capacity to avoid apoptosis despite genotoxic damage may underlie the persistence and malignant predisposition of Barrett's metaplasia. [Cancer Res 2009;69(2):672–7]