title: Targeting a novel onco-glycoprotein antigen at tumoral pancreatic cell surface by mAb16D10 induces cell death.
abstract: The mAb16D10 was raised against a pathological onco-glycoform of bile salt-dependent lipase isolated from the pancreatic juice of a patient suffering from a pancreatic adenocarcinoma. We previously showed that mAb16D10 specifically discriminates human pancreatic tumor tissues from other cancer and nontumor tissues. In this study, we report that mAb16D10 inhibited the proliferation of only human pancreatic tumor cells expressing 16D10 plasma membrane Ag. Interaction of mAb16D10 with its cognate surface Ag on pancreatic cells promoted cell death by activation of the p53- and caspase-dependent apoptotic pathway, and silencing of p53 decreased cell death. The decreased proliferation was also partly due to cell cycle arrest in G1/S phase, mAb16D10 triggering of glycogen synthase kinase-3β (GSK-3β) activation, degradation of β-catenin, and decreased expression of cyclin D1. GSK-3β positively affected p53 expression in pancreatic tumor cells after mAb16D10 binding. Inhibition of GSK-3β activity reversed the effects induced by mAb16D10 in SOJ-6 cells, supporting the pivotal role of GSK-3β signaling in the mechanisms of action induced by mAb16D10. Also, mAb16D10 cell treatment led to membrane overexpression of E-cadherin. Both E-cadherin and tumor Ag were localized in membrane lipid cholesterol-rich microdomains and are thought to belong to signaling platforms involved in the induction of cell cycle arrest and cell death. Overall, this study reveals that mAb16D10 holds great potential to prevent pancreatic tumor proliferation by apoptotic cell death, thus promising therapeutic prospects for treatment of pancreatic adenocarcinoma, a highly lethal disease.
authors.affiliation: Aix-Marseille Université, Centre de Recherche en Oncologie Biologique et Oncopharmacologie, F-13005, Marseille, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Crescence
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beraud
authors.forename: Veronique
authors.initials: V
authors.lastname: Sbarra
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bernard
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
authors.forename: Eric
authors.initials: E
authors.lastname: Mas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D008562:Membrane Glycoproteins