BCL–3 promotes cyclooxygenase–2/prostaglandin E2 signalling in colorectal cancer

Tracey Jane Collard, Hafsah Mohammed Fallatah, Alexander Greenhough, Christos Paraskeva, Ann Caroline Williams*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

First discovered as an oncogene in leukaemia, recent reports highlight an emerging role for the proto-oncogene BCL-3 in solid tumours. Importantly, BCL-3 expression is upregulated in >30% of colorectal cancer cases and is reported to be associated with a poor prognosis. However, the mechanism by which BCL-3 regulates tumorigenesis in the large intestine is yet to be fully elucidated. In the present study, it was shown for the first time that knocking down BCL–3 expression suppressed cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) signalling in colorectal cancer cells, a pathway known to drive several of the hallmarks of cancer. RNAi-mediated suppression of BCL-3 expression decreased COX-2 expression in colorectal cancer cells both at the mRNA and protein level. This reduction in COX–2 expression resulted in a significant and functional reduction (30-50%) in the quantity of pro-tumorigenic PGE2 produced by the cancer cells, as shown by enzyme linked immunoassays and medium exchange experiments. In addition, inhibition of BCL-3 expression also significantly suppressed cytokine–induced (TNF–α or IL-1β) COX-2 expression. Taken together, the results of the present study identified a novel role for BCL–3 in colorectal cancer and suggested that expression of BCL-3 may be a key determinant in the COX–2–meditated response to inflammatory cytokines in colorectal tumour cells. These results suggest that targeting BCL-3 to suppress PGE2 synthesis may represent an alternative or complementary approach to using non-steroidal anti-inflammatory drugs [(NSAIDs), which inhibit cyclooxygenase activity and suppress the conversion of arachidonic acid to prostaglandin], for prevention and/or recurrence in PGE2-driven tumorigenesis.

Original languageEnglish
Pages (from-to)1304-1313
Number of pages10
JournalInternational Journal of Oncology
Volume56
Issue number5
Early online date16 Mar 2020
DOIs
Publication statusPublished - 1 May 2020

Keywords

  • BCL-3
  • Colorectal cancer
  • COX-2
  • Hallmarks of cancer
  • PGE

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