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The proapoptotic BH3-only protein Bim is downregulated in a subset of colorectal cancers and is repressed by antiapoptotic COX-2/PGE2 signalling in colorectal adenoma cells

Oncogene volume 29, pages 3398–3410 (2010)Cite this article

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Abstract

Overexpression of cyclooxygenase-2 (COX-2) and elevated levels of its enzymatic product prostaglandin E2 (PGE2) occur in the majority of colorectal cancers and have important roles in colorectal tumorigenesis. However, despite the established prosurvival role of PGE2 in cancer, the underlying mechanisms are not fully understood. Here, we have shown that PGE2 suppresses apoptosis via repression of the proapoptotic BH3-only protein Bim in human colorectal adenoma cells. Repression of Bim expression was dependent upon PGE2-mediated activation of the Raf-MEK-ERK1/2 pathway, which promoted Bim phosphorylation and proteasomal degradation. Reduction of Bim expression using RNA interference reduced spontaneous apoptosis in adenoma cells and abrogated PGE2-dependent apoptosis suppression. Treatment of COX-2-expressing colorectal carcinoma cells with COX-2-selective NSAIDs-induced Bim expression, suggesting that Bim repression via PGE2 signalling may be opposed by COX-2 inhibition. Examination of Bim expression in two established in vitro models of the adenoma–carcinoma sequence revealed that downregulation of Bim expression was associated with tumour progression towards an anchorage-independent phenotype. Finally, immunohistochemical analyses revealed that Bim expression is markedly reduced in approximately 40% of human colorectal carcinomas in vivo. These observations highlight the COX-2/PGE2 pathway as an important negative regulator of Bim expression in colorectal tumours and suggest that Bim repression may be an important step during colorectal cancer tumorigenesis.

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Acknowledgements

We thank Debbie Martin and Gini Tilly for help with histology; David Huang for provision of Bim wild-type and null iMEF cells; Andy Silver and Nirosha Suraweera for sequencing analysis; Andy Herman for help with flow cytometry, and members of the CP group for useful discussion. This work was funded by the Citrina Foundation, the John James Bristol Foundation, and by a Cancer Research UK programme grant.

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  1. Department of Cellular and Molecular Medicine, Cancer Research UK Colorectal Tumour Biology Group, School of Medical Sciences, University of Bristol, UK

    A Greenhough, C A Wallam, D J Hicks, A C Williams & C Paraskeva

  2. Department of Clinical Pathology, Bristol Royal Infirmary, Bristol, UK

    M Moorghen

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  1. A Greenhough
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Correspondence to A Greenhough.

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Greenhough, A., Wallam, C., Hicks, D. et al. The proapoptotic BH3-only protein Bim is downregulated in a subset of colorectal cancers and is repressed by antiapoptotic COX-2/PGE2 signalling in colorectal adenoma cells. Oncogene 29, 3398–3410 (2010). https://doi.org/10.1038/onc.2010.94

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