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.