Cyclooxygenase-2 overexpression abrogates the antiproliferative effects of TGF-beta.
The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-beta for example in the intestine has been discussed as well as a preponderance or prolongation of growth factor stimulation. The experiments presented here demonstrated that COX-2 transfection of a TGF-beta-sensitive cell line abrogates the growth inhibitory effects of TGF-beta. However, analysis of the TGF-beta/Smad-signalling pathway clearly revealed that COX-2 overexpression did not interfere with that. Neither TGF-receptor expression nor Smad phosphorylation and signal transfer into the nucleus were influenced by COX-2 overexpression. In addition, a TGF-beta reporter assay revealed no difference between controls and COX-2-transfected cells. Thus, the proliferation inhibiting effects must have been well compensated by growth-inducing stimuli. Indications for this came from experiments showing an induction of TGF-alpha expression and secretion with a higher and prolonged stimulation of the ERK 1/2 (p42/44) pathway in COX-2 transfectants. This effect could have been triggered by direct prostaglandin receptor stimulation or changes in intracellular lipid mediators. An increase in PPAR signalling as proven by a reporter assay is indication for the latter. Therefore, inhibiting both COX-2 as well as the PPAR and TGF/EGF pathway could be effective in the inhibition of adenoma or even carcinoma development in the intestine.
Enders
G A
GA
Institute for Surgical Research, LMU-München, Marchioninistr. 27, München D-81366, Germany. enders@med.uni-muenchen.de
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D008907:Mink; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D010703:Phorbol Esters; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3