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Death Receptor-3, a New E-Selectin Counter-Receptor that Confers Migration and Survival Advantages to Colon Carcinoma Cells by Triggering p38 and ERK MAPK Activation

Le Centre de Recherche en Cancérologie de l'Université Laval, Québec PQ, Canada

Requests for reprints: Jacques Huot, Le Centre de Recherche en Cancérologie de l'Université Laval, 9 rue McMahon, Quebec City, Quebec, Canada G1R-2J6. Phone: 418-525-4444-15553; Fax: 418-691-5439; E-mail: Jacques.Huot{at}phc.ulaval.ca.

E-selectin-mediated adhesion of colon cancer cells to endothelial cells is a key event in metastasis. However, the signaling mechanisms that confer metastatic advantages to cancer cells adhering to E-selectin are ill defined. By using affinity column chromatography and pull-down assays on purified membrane extracts of HT29 and LoVo cells coupled to mass spectrometry analysis, we obtained the first evidence indicating that E-selectin binds to death receptor-3 (DR3) expressed by the cancer cells. Thereafter, we accumulated several results, suggesting that DR3 is an E-selectin receptor on colon cancer cells and that its activation by E-selectin triggers the activation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) and confers migration and survival advantages. First, by Western blotting, we found that the E-selectin-binding protein, identified as DR3, is recognized by two anti-DR3 antibodies. Second, the neutralization of DR3 with an antibody and its knockdown by small interfering RNA decrease the adhesion of colon cancer cells to E-selectin and E-selectin-expressing human umbilical vein endothelial cells. Third, inhibiting DR3 and knocking down its expression impair transendothelial migration of HT29 cells and block the activation of p38 and ERK by E-selectin. Fourth, high molecular weight isoforms of DR3 are expressed in samples of primary human colon carcinoma but not in samples from normal colon tissue. Intriguingly, DR3 is a death receptor but its activation by E-selectin does not induce apoptosis in colon cancer cells, except when ERK is inhibited. Our findings identify novel signaling and functional roles of DR3 activated in response to E-selectin and highlight the potential link between DR3 and metastasis. (Cancer Res 2006; 66(18): 9117-24)