Nucleoside analogs induce proteasomal down-regulation of p21 in chronic lymphocytic leukemia cell lines

Autor: E. de Viron, Laurent Bastin-Coyette, Sabine Cardoen, E. Van Den Neste, Angélique Arts, Rachid Amsailale, Françoise Bontemps, Caroline Smal
Přispěvatelé: de Duve Institute and Université catholique de Louvain, Université Catholique de Louvain = Catholic University of Louvain (UCL)-de Duve Institute, Department of Hematology, Cliniques Universitaires Saint-Luc [Bruxelles]
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
p53
Cdk2
Proteasome Endopeptidase Complex
Cell cycle checkpoint
Chronic lymphocytic leukemia
Cell
Down-Regulation
Antineoplastic Agents
Biology
Biochemistry
03 medical and health sciences
PCNA monoubiquitination
0302 clinical medicine
Cell Line
Tumor
Proliferating Cell Nuclear Antigen
p21 depletion
medicine
Cytotoxic T cell
Humans
030304 developmental biology
Pharmacology
0303 health sciences
Kinase
CLL
Cyclin-dependent kinase 2
Cyclin-Dependent Kinase 2
Ubiquitination
Purine Nucleosides
medicine.disease
Leukemia
Lymphocytic
Chronic
B-Cell
3. Good health
Up-Regulation
Enzyme Activation
medicine.anatomical_structure
Cell culture
Apoptosis
030220 oncology & carcinogenesis
Cancer research
biology.protein
Cladribine
Nucleoside analogs
Tumor Suppressor Protein p53
Vidarabine
Zdroj: Biochemical Pharmacology
Biochemical Pharmacology, Elsevier, 2011, 81 (5), pp.586. ⟨10.1016/j.bcp.2010.12.009⟩
ISSN: 0006-2952
1873-2968
DOI: 10.1016/j.bcp.2010.12.009⟩
Popis: International audience; Nucleoside analogs (NAs) represent an important class of anticancer agents that induce cell death after conversion to triphosphate derivatives. One of their most important mechanisms of action is the activation of p53, leading to apoptosis through the intrinsic pathway. Classically, the activation of p53 also induces p21 accumulation, which leads to cell cycle arrest at the G1/S transition. In previous work, we observed that 2-chloro-2′-deoxyadenosine (CdA), a NA with high activity in lymphoid disorders, including chronic lymphocytic leukemia (CLL), promotes the G1/S transition in the CLL cell line EHEB at cytotoxic concentrations. This finding le us to investigate the p21 response to NAs in these cells. We show here that CdA, but also fludarabine, gemcitabine, and cytarabine, strongly reduced the p21 protein level in EHEB cells as well as in JVM-2 cells, another CLL cell line. This p21 depletion occurred despite induction of p53 and increase of p21 mRNA and was prevented by proteasome inhibitors. Increase of proteasomal degradation caused by NAs appeared to be ubiquitin-independent. Also, NAs induced in these cells an increase of cyclin-dependent kinase (Cdk2) activity and a monoubiquitination of cell proliferating nuclear antigen (PCNA), two processes that are negatively regulated by p21. These changes were not observed with other p53 activators, like etoposide and nutlin-3a that increased the p21 protein level. In conclusion, our study reveals that NAs can induce an alternative pattern of cellular response in some cell models.
Databáze: OpenAIRE
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