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

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

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.

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2020
• Online Publication Date: Mar 16, 2020
• Publication Date: May 1, 2020
• Deposit Date: Jan 19, 2021
• Publicly Available Date: Mar 17, 2021
• Journal: International Journal of Oncology
• Print ISSN: 1019-6439
• Electronic ISSN: 1791-2423
• Publisher: Spandidos Publications
• Peer Reviewed: Peer Reviewed
• Volume: 56
• Issue: 5
• Pages: 1304-1313
• DOI: https://doi.org/10.3892/ijo.2020.5013
• Public URL: https://uwe-repository.worktribe.com/output/7002184