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MUCOSAL BIOLOGY

CUGBP2 downregulation by prostaglandin E₂ protects colon cancer cells from radiation-induced mitotic catastrophe

Departments of ¹Medicine, ²Otorhinolaryngology, and ³Cell Biology, and ⁴OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City; and ⁵Department of Veteran Affairs Medical Center, Oklahoma City, Oklahoma

Submitted 24 January 2008 ; accepted in final form 2 March 2008

Prostaglandin E₂ (PGE₂) is a potent inhibitor of ionizing radiation (IR)-induced cell death. Exposure of colon cancer cells to IR leads to increased CUGBP2 expression. Therefore, we tested the hypothesis that PGE₂ radioprotects colon cancer cells by inhibiting CUGBP2 expression. Exposure of HCT-116 cells to -IR (0–12 Gy) resulted in a dose-dependent reduction in cell growth and an increase in the G₂-M phase of the cell cycle. Western blot analyses demonstrated increased levels of activated caspase 9 and caspase 3. In addition, whereas Bax expression is increased, that of Bcl-2 and Bcl-x_L was reduced. Further analyses demonstrated increased activation of Chk1 and Chk2 kinases, coupled with higher levels of nuclear cyclin B1 and Cdc2. Pretreatment with PGE₂ suppressed the activation of caspase 3 and caspase 7 and inhibited Bax expression. In addition, PGE₂ treatment restored growth and colony formation to control levels. IR significantly upregulated the expression of CUGBP2 in the cells, which was suppressed when cells were pretreated with PGE₂. Ectopic overexpression of CUGBP2 also induced apoptosis. Furthermore, it reversed the PGE₂-mediated protection from IR-induced mitotic catastrophe. Furthermore, there was an increase in nuclear localization of cyclin B1 and Cdc2 coupled with increased phosphorylation of p53, Chk1, Chk2, and Cdc25c proteins. Cell cycle analysis also demonstrated increased G₂-M transition. In contrast, siRNA-mediated suppression of CUGBP2 expression restored normal cell cycle progression and decreased IR-induced apoptosis. Taken together, these data demonstrate that PGE₂ protects colon cancer cells from IR-induced mitotic catastrophe in part through suppression of CUGBP2 expression.

cell cycle; apoptosis; caspase; check point kinases; RNA binding protein