Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells.
Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma subtype, characterized by overexpression of cyclin D1 as a consequence of the chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The present study investigated the effect of a specific proteasome inhibitor, lactacystin, on cell cycle progression and apoptosis in two lymphoma cell lines harbouring the t(11;14)(q13;q32) and additional cytogenetic alterations, including p53 mutation (NCEB) and p16 deletion (Granta 519). Granta cells were more susceptible to inhibition of the proteasome with respect to inhibition of proliferation and apoptosis induction. No changes were observed in the expression levels of the G1 regulatory molecules cyclin D1 and cdk4, but cell cycle arrest and apoptosis induction was accompanied by accumulation of the cdk inhibitor p21 in both cell lines. Increased p53 expression was only observed in Granta cells with wild-type p53. Cleavage of procaspase-3 and -9 was observed but cleavage of procaspase-8 was not involved in apoptosis induction. The proapoptotic effect of lactacystin was reversed by pretreatment with the pancaspase inhibitor zVAD.fmk. Lactacystin was also effective in inducing apoptosis in lymphoma cells from MCL patients. We conclude that inhibition of the proteasome might be a promising therapeutic approach for this incurable disease.
Bogner
Christian
C
Third Department of Medicine, Technical University of Munich, Munich, Germany.
Ringshausen
Ingo
I
Schneller
Folker
F
Fend
Falko
F
Quintanilla-Martinez
Leticia
L
Häcker
Georg
G
Goetze
Katharina
K
Oostendorp
Robert
R
Peschel
Christian
C
Decker
Thomas
T
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D011480:Protease Inhibitors; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D000111:Acetylcysteine