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INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France;
* The Laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium;
Novo Nordisk, Bagsvaerd, DK-2880, Denmark;
Department of Pathology, University of Newcastle, Newcastle upon Tyne NE1 4LP, UK; and
INSERM U452, Biologie Cellulaire et Moléculaire des Microorganismes Pathogènes et de leurs Toxines, UFR de Médecine, 06107, Nice Cedex, France
2Correspondence: INSERM Unit U482, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: gespach{at}st-antoine.inserm.fr
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
q (AGq), G12, G13
(AG12/13), 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 TXA2-R-dependent
invasion pathway, which is monitored via a Rho- and
G12/G13-independent mechanism using the Gq/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.—Rodrigues, S., Nguyen, Q.-D.,
Faivre, S., Bruyneel, E., Thim, L., Westley, B., May, F., Flatau, G.,
Mareel, M., Gespach, C., Emami, S. Activation of cellular invasion by
trefoil peptides and src is mediated by cyclooxygenase- and thromboxane
A2 receptor-dependent signaling pathways.
Key Words: inflammation • cancer progression • heterotrimeric G-proteins • Rho-like GTPases • phospholipase C
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