title: Resistance to TRAIL in mantle cell lymphoma cells is associated with the decreased expression of purine metabolism enzymes.
abstract: Mantle cell lymphoma (MCL) is a rare aggressive type of B-cell non-Hodgkin's lymphoma. Response to chemotherapy tends to be short and virtually all patients sooner or later relapse. The prognosis of relapsed patients is extremely poor. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered one of the novel experimental molecules with strong antitumor effects. TRAIL triggers extrinsic apoptotis in tumor cells by binding to TRAIL 'death receptors' on the cell surface. Recombinant TRAIL has shown promising pro-apoptotic effects in a variety of malignancies including lymphoma. However, as with other drugs, lymphoma cells can develop resistance to TRAIL. Therefore, the aim of this study was to identify the molecular mechanisms responsible for, and associated with TRAIL resistance in MCL cells. If identified, these features may be used as molecular targets for the effective elimination of TRAIL-resistant lymphoma cells. From an established TRAIL-sensitive mantle cell lymphoma cell line (HBL-2) we derived a TRAIL-resistant HBL-2/R subclone. By TRAIL receptor analysis and differential proteomic analysis of HBL-2 and HBL-2/R cells we revealed a marked downregulation of all TRAIL receptors and, among others, the decreased expression of 3 key enzymes of purine nucleotide metabolism, namely purine nucleoside phosphorylase, adenine phosphoribosyltransferase and inosine-5'-monophosphate dehydrogenase 2, in the resistant HBL-2/R cells. The downregulation of the 3 key enzymes of purine metabolism can have profound effects on nucleotide homeostasis in TRAIL-resistant lymphoma cells and can render such cells vulnerable to any further disruption of purine nucleotide metabolism. This pathway represents a 'weakness' of the TRAIL-resistant MCL cells and has potential as a therapeutic target for the selective elimination of such cells.
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, 128 53 Prague, Czech Republic. jana.pospisilova@lf1.cuni.cz
authors.forename: Jana
authors.initials: J
authors.lastname: Pospisilova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Vit
authors.forename: Lucie
authors.initials: L
authors.lastname: Lorkova
authors.forename: Magdalena
authors.initials: M
authors.lastname: Klanova
authors.forename: Jan
authors.initials: J
authors.lastname: Zivny
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.forename: Jiri
authors.initials: J
authors.lastname: Petrak
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015180:Electrophoresis, Gel, Two-Dimensional; D005434:Flow Cytometry; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D040901:Proteomics; D011687:Purines / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015203:Reproducibility of Results; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D009363:Neoplasm Proteins; D011687:Purines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C030985:purine