Abstract
Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E2 (PGE2) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAFV595E mutation. However, mechanisms underlying aberrant PGE2 production in BRAFV595E cUC patients remain unclear. Drug screening revealed that inhibition of RAF/MEK/ERK pathway, p38 and JNK pathway reduced PGE2 production in cUC cells. By pharmacological inhibition of the multiple components in the pathway, activation of the ERK MAPK pathway was shown to mediate overexpression of COX2 and production of PGE2 in BRAFV595E cUC cells. In silico gain-of-function analysis of the BRAF mutation also implicated involvement of mutation in the process. The positive association between ERK activation and COX2 expression was further validated in the clinical patients. Moreover, it was also suggested that p38 and JNK regulates PGE2 production independently of ERK pathway, possibly through COX2-dependent and COX1-/COX2- independent manner, respectively. In conclusion, this study demonstrated that activation of ERK induces production of PGE2 in BRAFV595E cUC cells, which is also independently regulated by p38 and JNK. With its unique vulnerability to COX-targeted therapy, BRAFV595E cUC may serve as a valuable model to study the tumour-promoting inflammation.
Highlights
Cancer-promoting inflammation is an important event in cancer development
We investigated the contribution of the ERK mitogen-activated protein kinase (MAPK) pathway in the regulation of the cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis including various Canine urothelial carcinoma (cUC) cell line, most of which harboured BRAFV595E mutation
We previously reported that cUC cell lines overexpress PGE213
Summary
Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E2 (PGE2) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. The pathway that induces upregulation of COX2/PGE2 axis in cUC cells was not elucidated Another characteristic of cUC is that a single nucleotide mutation in the BRAF gene, V595E, is detected in 70%–80% of canine patients[14,15]. BRAF is an isoform of RAF serine/threonine kinase, which belongs to the RAF/ MEK/ERK mitogen-activated protein kinase (MAPK) pathway This pathway is one of the most important signalling pathways that transmit extracellular signals to cell nuclei, thereby regulating cell proliferation, differentiation, survival and various other cellular functions. Canine BRAFV595E is suggested to contribute to constitutive activation of the ERK MAPK signalling cascade, its importance in cUC progression remains unclear. We investigated the contribution of the ERK MAPK pathway in the regulation of the COX2/PGE2 axis including various cUC cell line, most of which harboured BRAFV595E mutation. Our findings indicate a novel association between the activation of the ERK MAPK pathway in BRAF mutant cUC cells and dysregulation of the COX2/PGE2 axis
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