Article

CUGBP2 downregulation by prostaglandin E-2 protects colon cancer cells from radiation-induced mitotic catastrophe

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 06/2008; 294(5):G1235-44. DOI: 10.1152/ajpgi.00037.2008
Source: PubMed

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.

Download full-text

Full-text

Available from: Lurdes Queimado, Jul 01, 2015
0 Followers
 · 
99 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pilocytic astrocytomas (PAs) are World Health Organization Grade I gliomas; they most often affect children and young adults and occur in patients with neurofibromatosis type 1 (NF1). To identify genes that are differentially expressed in sporadic (S-PA) versus NF1-associated PAs (NF1-PAs) and those that might reflect differences in clinical behavior, we performed gene expression profiling using Affymetrix U133 Plus2.0 GeneChip arrays in 36 S-PAs and 11 NF1-PAs. Thirteen genes were overexpressed, and another 13 genes were underexpressed in NF1-PAs relative to S-PAs. Immunohistochemical studies performed on 103 tumors, representing 2 independently generated tissue microarrays, confirmed the differential expression of CUGBP2 (p = 0.0014), RANBP9 (p = 0.0075), ITGAV1 (p = 0.0001), and INFGR1 (p = 0.024) proteins. One of the underexpressed genes, aldehyde dehydrogenase 1 family member L1 (ALDH1L1), was also reduced in clinically aggressive compared with typical PAs (p = 0.01) and in PAs with increased cellularity and necrosis. Furthermore, in an additional independent set of tumors, weak to absent ALDH1L1 expression was found in 13 (72%) of 18 clinically aggressive PAs, in 8 (89%) of 9 PAs with pilomyxoid features, in 7 (70%) of 10 PAs with anaplastic transformation, and in 16 (76%) of 21 diffusely infiltrating astrocytomas of various grades. In summary, we have identified a molecular signature that distinguishes NF1-PA from S-PA and found that ALDH1L1 underexpression is associated with aggressive histology and/or biologic behavior.
    Journal of Neuropathology and Experimental Neurology 12/2008; 67(12):1194-204. DOI:10.1097/NEN.0b013e31818fbe1e · 4.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RNA-binding proteins (RBPs) play key roles in the posttranscriptional regulation of gene expression. RBPs control various posttranscriptional events, including splicing, polyadenylation, mRNA stability, transport, and translation. It is becoming apparent that RBPs play a significant role in pathophysiologic conditions such as inflammation and cancer. More importantly, we and others have begun dissecting the role of mRNA stability and translation in regulating gene expression, dysregulation of which has serious consequences for the fate of the cell. In this article, we discuss this emerging area of posttranscriptional gene regulation and the role of RBPs in the aberrant expression of proteins in tumorigenesis.
    Current Colorectal Cancer Reports 03/2010; 6(2):68-73. DOI:10.1007/s11888-010-0048-z
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated levels of RNA binding protein HuR were found in various human cancers. However, the mechanisms underlying HuR over-expression in cancers have not been fully elucidated. Here, we show that miR-16 acts as a novel post-transcriptional regulator for HuR. Knockdown of miR-16 increased HuR protein levels in MDA-MB-231 cells, while over-expression of pre-miR16 reduced HuR expression. Neither knockdown nor over-expression of miR-16 could alter the mRNA levels of HuR. Instead, knockdown of miR-16 increased the level of de novo synthesized HuR protein. Importantly, mechanistic studies showed that miR-16 associated with the 3'UTR of HuR, and knockdown of miR-16 markedly increased the luciferase activity of a HuR 3'UTR-containing reporter. We further demonstrate that the level of miR-16 was inversely correlated with HuR protein level in human breast carcinoma. Together, our results suggest an important role of miR-16 in regulating HuR translation and link this regulatory pathway to human breast cancer.
    Journal of Cellular Biochemistry 10/2010; 111(3):727-34. DOI:10.1002/jcb.22762 · 3.37 Impact Factor