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Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer
BACKGROUND: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. METHODS: Microar...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720240/ https://www.ncbi.nlm.nih.gov/pubmed/19638987 http://dx.doi.org/10.1038/sj.bjc.6605144 |
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author | Doherty, G A Byrne, S M Austin, S C Scully, G M Sadlier, D M Neilan, T G Kay, E W Murray, F E Fitzgerald, D J |
author_facet | Doherty, G A Byrne, S M Austin, S C Scully, G M Sadlier, D M Neilan, T G Kay, E W Murray, F E Fitzgerald, D J |
author_sort | Doherty, G A |
collection | PubMed |
description | BACKGROUND: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. METHODS: Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17β, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR. RESULTS: Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=−0.68, R(2)=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment. CONCLUSION: DRAK2 is a serine–threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival. |
format | Text |
id | pubmed-2720240 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-27202402010-08-04 Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer Doherty, G A Byrne, S M Austin, S C Scully, G M Sadlier, D M Neilan, T G Kay, E W Murray, F E Fitzgerald, D J Br J Cancer Molecular Diagnostics BACKGROUND: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. METHODS: Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17β, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR. RESULTS: Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=−0.68, R(2)=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment. CONCLUSION: DRAK2 is a serine–threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival. Nature Publishing Group 2009-08-04 2009-07-28 /pmc/articles/PMC2720240/ /pubmed/19638987 http://dx.doi.org/10.1038/sj.bjc.6605144 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Molecular Diagnostics Doherty, G A Byrne, S M Austin, S C Scully, G M Sadlier, D M Neilan, T G Kay, E W Murray, F E Fitzgerald, D J Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title | Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title_full | Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title_fullStr | Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title_full_unstemmed | Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title_short | Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer |
title_sort | regulation of the apoptosis-inducing kinase drak2 by cyclooxygenase-2 in colorectal cancer |
topic | Molecular Diagnostics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720240/ https://www.ncbi.nlm.nih.gov/pubmed/19638987 http://dx.doi.org/10.1038/sj.bjc.6605144 |
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