Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma

• Published in: Scientific reports Vol. 10; no. 1; p. 7826
• Main Authors: Yoshitake, Ryohei, Saeki, Kohei, Eto, Shotaro, Shinada, Masahiro, Nakano, Rei, Sugiya, Hiroshi, Endo, Yoshifumi, Fujita, Naoki, Nishimura, Ryohei, Nakagawa, Takayuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2020; Nature Publishing Group
• Subjects: 13/51; 631/67/589/1336; 692/4028/67/589/1336; 96/95; Bladder cancer; Cyclooxygenase-1; Cyclooxygenase-2; Drug screening; Extracellular signal-regulated kinase; Humanities and Social Sciences; MAP kinase; Metabolic pathways; multidisciplinary; Mutation; Prostaglandin E2; Raf protein; Science; Science (multidisciplinary); Tumors; Urothelial cancer; Urothelial carcinoma
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-64832-5

Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E 2 (PGE 2 ) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAF V595E mutation. However, mechanisms underlying aberrant PGE 2 production in BRAF V595E cUC patients remain unclear. Drug screening revealed that inhibition of RAF/MEK/ERK pathway, p38 and JNK pathway reduced PGE 2 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 PGE 2 in BRAF V595E 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 PGE 2 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 PGE 2 in BRAF V595E cUC cells, which is also independently regulated by p38 and JNK. With its unique vulnerability to COX-targeted therapy, BRAF V595E cUC may serve as a valuable model to study the tumour-promoting inflammation.