Resistance to TRAIL in mantle cell lymphoma cells is associated with the decreased expression of purine metabolism enzymes
Language English Country Greece Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Electrophoresis, Gel, Two-Dimensional MeSH
- Cell Membrane metabolism MeSH
- Cell Death drug effects MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Humans MeSH
- Lymphoma, Mantle-Cell enzymology pathology MeSH
- Cell Line, Tumor MeSH
- Neoplasm Proteins metabolism MeSH
- TNF-Related Apoptosis-Inducing Ligand pharmacology MeSH
- Proteomics MeSH
- Flow Cytometry MeSH
- Purines metabolism MeSH
- Reproducibility of Results MeSH
- Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Neoplasm Proteins MeSH
- TNF-Related Apoptosis-Inducing Ligand MeSH
- purine MeSH Browser
- Purines MeSH
- Receptors, TNF-Related Apoptosis-Inducing Ligand MeSH
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.
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