Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase- and thromboxane A2 receptor-dependent signaling pathways.
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 Galphaq (AGalphaq), Galpha12, Galpha13 (AGalpha12/13), 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 Galpha12/Galpha13-independent mechanism using the Galphaq/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
S
INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
Nguyen
Q D
QD
Faivre
S
S
Bruyneel
E
E
Thim
L
L
Westley
B
B
May
F
F
Flatau
G
G
Mareel
M
M
Gespach
C
C
Emami
S
S
D002461:Cell Line, Transformed; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006133:Growth Substances / Q000494:pharmacology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D008565:Membrane Proteins; D009077:Mucins; D009124:Muscle Proteins; D009361:Neoplasm Invasiveness; D009479:Neuropeptides; D010455:Peptides / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D010738:Type C Phospholipases / Q000378:metabolism
D017077:Culture Media, Conditioned; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006133:Growth Substances; D007527:Isoenzymes; D008565:Membrane Proteins; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; D017482:Receptors, Thromboxane; C051838:TFF1 protein, human; C099037:TFF3 protein, rat; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D016392:Proto-Oncogene Proteins pp60(c-src); D010738:Type C Phospholipases; D020558:GTP Phosphohydrolases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins