Unlike esophageal squamous cells, Barrett's epithelial cells resist apoptosis by activating the nuclear factor-kappaB pathway.
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-kappaB (NF-kappaB) 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-kappaB, Bcl-2, XIAP, cIAP-1, and survivin proteins. We also used Bay 11-7085 and siRNAs to NF-kappaB and Bcl-2 to assess the effects of NF-kappaB and Bcl2 inhibition on apoptosis. UV-B irradiation at low doses (50 and 100 J/m(2)) 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-kappaB, 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-kappaB and was decreased significantly by siRNA for Bcl-2. We conclude that the ability of Barrett's epithelial cells to activate the NF-kappaB 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.
Hormi-Carver
Kathy
K
Department of Medicine, VA North Texas Health Care System, University of Texas Southwestern Medical School, Dallas, Texas 75216, USA.
Zhang
Xi
X
Zhang
Hui Ying
HY
Whitehead
Robert H
RH
Terada
Lance S
LS
Spechler
Stuart J
SJ
Souza
Rhonda F
RF
D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005764:Gastroesophageal Reflux / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D014466:Ultraviolet Rays
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2