TY - JOUR
T1 - BCL–3 promotes cyclooxygenase–2/prostaglandin E2 signalling in colorectal cancer
AU - Collard, Tracey Jane
AU - Fallatah, Hafsah Mohammed
AU - Greenhough, Alexander
AU - Paraskeva, Christos
AU - Williams, Ann Caroline
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
KW - BCL-3
KW - Colorectal cancer
KW - COX-2
KW - Hallmarks of cancer
KW - PGE
UR - http://www.scopus.com/inward/record.url?scp=85081898342&partnerID=8YFLogxK
U2 - 10.3892/ijo.2020.5013
DO - 10.3892/ijo.2020.5013
M3 - Article (Academic Journal)
C2 - 32319612
AN - SCOPUS:85081898342
SN - 1019-6439
VL - 56
SP - 1304
EP - 1313
JO - International Journal of Oncology
JF - International Journal of Oncology
IS - 5
ER -