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CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2008 May; Vol. 294 (5), pp. G1235-44. Date of Electronic Publication: 2008 Mar 06. - Publication Year :
- 2008
-
Abstract
- Prostaglandin E(2) (PGE(2)) 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 PGE(2) radioprotects colon cancer cells by inhibiting CUGBP2 expression. Exposure of HCT-116 cells to gamma-IR (0-12 Gy) resulted in a dose-dependent reduction in cell growth and an increase in the G(2)-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 PGE(2) suppressed the activation of caspase 3 and caspase 7 and inhibited Bax expression. In addition, PGE(2) 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 PGE(2). Ectopic overexpression of CUGBP2 also induced apoptosis. Furthermore, it reversed the PGE(2)-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 G(2)-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 PGE(2) protects colon cancer cells from IR-induced mitotic catastrophe in part through suppression of CUGBP2 expression.
- Subjects :
- Apoptosis drug effects
Apoptosis radiation effects
CELF Proteins
Caspase 7 metabolism
Caspase 9 metabolism
Cell Cycle drug effects
Cell Cycle radiation effects
Cell Proliferation drug effects
Cell Proliferation radiation effects
Checkpoint Kinase 1
Checkpoint Kinase 2
Cyclin B metabolism
Down-Regulation
Gamma Rays
HCT116 Cells
Histones metabolism
Humans
Nerve Tissue Proteins genetics
Phosphorylation drug effects
Phosphorylation radiation effects
Protein Kinases metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
RNA, Small Interfering genetics
RNA-Binding Proteins genetics
bcl-2-Associated X Protein metabolism
bcl-X Protein metabolism
cdc25 Phosphatases metabolism
Dinoprostone pharmacology
Mitosis drug effects
Mitosis radiation effects
Nerve Tissue Proteins metabolism
RNA-Binding Proteins metabolism
Radiation-Protective Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1857
- Volume :
- 294
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 18325984
- Full Text :
- https://doi.org/10.1152/ajpgi.00037.2008