title: Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1beta)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILbeta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.
authors.affiliation: Clinic of Internal Medicine, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, Kiel, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sebens Müerköster
authors.forename: V
authors.initials: V
authors.lastname: Werbing
authors.forename: B
authors.initials: B
authors.lastname: Sipos
authors.forename: M A
authors.initials: MA
authors.lastname: Debus
authors.forename: M
authors.initials: M
authors.lastname: Witt
authors.forename: M
authors.initials: M
authors.lastname: Grossmann
authors.forename: D
authors.initials: D
authors.lastname: Leisner
authors.forename: J
authors.initials: J
authors.lastname: Kötteritzsch
authors.forename: H
authors.initials: H
authors.lastname: Kappes
authors.forename: G
authors.initials: G
authors.lastname: Klöppel
authors.forename: P
authors.initials: P
authors.lastname: Altevogt
authors.forename: U R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D053583:Interleukin-1beta; D039842:Neural Cell Adhesion Molecule L1; D009569:Nitric Oxide; D005047:Etoposide; D052247:Nitric Oxide Synthase Type II; D020169:Caspases