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Lookup NU author(s): Professor Bruce Westley,
Dr Felicity May
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We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors (TFFs), src, and the cyclooxygenases COX-1 and COX-2. Pharmacological inhibitors of the Rho small GTPase (C3 exoenzyme), phospholipase C (U-73122), cyclooxygenases (SC-560, NS-398), and the thromboxane A2 receptor (TXA2-R) antagonist SQ-295 completely abolished invasion induced by intestinal trefoil factor, pS2, and src in kidney and colonic epithelial cells MDCKts.src and PCmsrc. In contrast, invasion was induced by the TXA2-R mimetic U-46619, constitutively activated forms of the heterotrimeric G-proteins G alphaq (AG alphaq), G alpha 12, G alpha 13 (AG alpha 12/13), which are signaling elements downstream of TXA2-R. Ectopic overexpression of pS2 cDNA and protein in MDCKts.src-pS2 cells and human colorectal cancer cells HCT8/S11-pS2 initiate distinct invasion signals that are Rho independent and COX and TXA2-R dependent. We detected a marked induction of COX-2 protein and accumulation of the stable PGH2/TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src. This led to activation of the TXA2R-dependent invasion pathway, which is monitored via a Rho- and G alpha 12/G alpha 13-independent mechanism using the G alphaq/PKC signaling cascade. These findings identify a new intracrine/paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers.
Author(s): Rodrigues S, Nguyen QD, Faivre S, Bruyneel E, Thim L, Westley B, May F, Flatau G, Mareel M, Gespach C, Emami S
Publication type: Article
Publication status: Published
Journal: The FASEB Journal
ISSN (print): 0892-6638
ISSN (electronic): 1530-6860
Publisher: Federation of American Societies for Experimental Biology
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