In non-neoplastic Barrett's epithelial cells, acid exerts early antiproliferative effects through activation of the Chk2 pathway

Hui Ying Zhang, Xi Zhang, Kathy Hormi-Carver, Linda A. Feagins, Stuart J. Spechler, Rhonda F. Souza

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19 Scopus citations

Abstract

Acid exerts pro-proliferative effects in Barrett's-associated esophageal adenocarcinoma cells. In non-neoplastic Barrett's epithelial (BAR-T) cells, in contrast, we have shown that acid exposure has antiproliferative effects. To explore our hypothesis that the acid-induced, antiproliferative effects are mediated by alterations in the proteins that regulate the G1-S cell cycle checkpoint, we exposed non-neoplastic Barrett's cells to acidic media (pH 4.0) and analyzed G1-S checkpoint proteins' expression, phosphorylation, and activity levels by Western blot. We studied acid effects on growth (by cell counts), proliferation (by flow cytometry and bromodeoxyuridine incorporation), cell viability (by trypan blue staining), and apoptosis (byannexin V staining), and we used caffeine and small interfering RNA to assess the effects of checkpoint kinase 2 (Chk2) inhibition on G1-S progression. Acid exposure significantly decreased cell numbers without affecting cell viability and with only a slight increase in apoptosis. Within 2 h of acid exposure, there was a delay in progression through the G1-S checkpoint that was associated with increased phosphorylation of Chk2, decreased levels of Cdc25A, and decreased activity of cyclin E-cyclin-dependent kinase 2; by 4 h, a continued delayat G1-S was associated with increased expression of p53 and p21. Caffeine and Chk2 siRNA abolished the acid-induced G1-S delayat 2 but not at 4 h. We conclude that acid exposure in non-neoplastic BAR-T cells causes early antiproliferative effects that are mediated by the activation of Chk2. Thus, we have elucidated a mechanism whereby acid can exert disparate effects on proliferation in neoplastic and non-neoplastic BAR-T cells.

Original languageEnglish (US)
Pages (from-to)8580-8587
Number of pages8
JournalCancer research
Volume67
Issue number18
DOIs
StatePublished - Sep 15 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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