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

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.

The impact of damage-associated molecules released from canine tumor cells on gene expression in macrophages

“…3 A). This observation may reflect our previous result that the COX genes are highly expressed in these cell lines 20 , 21 .…”

Detection of indoleamine 2,3-dioxygenase 1-expressing cells in canine normal and tumor tissues

“…In contrast, in TCC, SCC, and ASAC, the expression of IDO1 in tumor cells was broad and diffuse, suggesting that the activation of the IDO1 in these tumors is constitutive, rather than induced by environmental factors. In canine tumors, constitutive expression of PGE2 has been reported in TCC [9,27], and these previous reports may support our hypothesis that auto-paracrine PGE2 signaling drives the overexpression of IDO1 in canine TCC. These results suggest that canine tumors acquire the mechanism of immune escape via activation of acquired or intrinsic IDO1 expression.…”

<p>MAGOH/MAGOHB Inhibits the Tumorigenesis of Gastric Cancer via Inactivation of b-RAF/MEK/ERK Signaling</p>

“…28 Abnormal expression of the b-RAF/MRK/ ERK signaling pathway is related with the progression of a number of malignancies. [29][30][31] In addition, some signaling pathways spread through b-RAF/MEK/ERK in various cellular processes, such as cell growth, differentiation and apoptosis. [32][33][34] Our research was consistent with these data, suggesting that double knockdown of MAGOH and MAGOHB inhibited the growth of gastric cancer cells via downregulation of b-RAF/MEK/ERK signaling.…”