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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-09, Vol.66 (18), p.9117-9124
• Main Authors: GOUT, Stéphanie, MORIN, Chantale, HOULE, Francois, HUOT, Jacques
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis - physiology; Biological and medical sciences; Cell Movement - physiology; Cell Survival - physiology; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; E-Selectin - metabolism; Endothelial Cells - cytology; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; HT29 Cells; Humans; Medical sciences; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Receptors, Tumor Necrosis Factor, Member 25 - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4605

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.