Crosstalk among Bcl-2 family members in B-CLL: seliciclib acts via the Mcl-1/Noxa axis and gradual exhaustion of Bcl-2 protection

D. Y. H. Hallaert, R. Spijker, M. Jak, I. A. M. Derks, N. L. Alves, F. M. Wensveen, J. P. de Boer, D. de Jong, S. R. Green, M. H. J. van Oers, E. Eldering

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Seliciclib (R-roscovitine) is a cyclin-dependent kinase inhibitor in clinical development. It triggers apoptosis by inhibiting de novo transcription of the short-lived Mcl-1 protein, but it is unknown how this leads to Bax/Bak activation that is required for most forms of cell death. Here, we studied the effects of seliciclib in B-cell chronic lymphocytic leukemia (B-CLL), a malignancy with aberrant expression of apoptosis regulators. Although seliciclib-induced Mcl-1 degradation within 4 h, Bax/Bak activation occurred between 16 and 20 h. During this period, no transcriptional changes in apoptosis-related genes occurred. In untreated cells, prosurvival Mcl-1 was engaged by the proapoptotic proteins Noxa and Bim. Upon drug treatment, Bim was quickly released. The contribution of Noxa and Bim as a specific mediator of seliciclib-induced apoptosis was demonstrated via RNAi. Significantly, 16 h after seliciclib treatment, there was accumulation of Bcl-2, Bim and Bax in the 'mitochondria-rich' insoluble fraction of the cell. This suggests that after Mcl-1 degradation, the remaining apoptosis neutralizing capacity of Bcl-2 is gradually overwhelmed, until Bax forms large multimeric pores in the mitochondria. These data demonstrate in primary leukemic cells hierarchical binding and crosstalk among Bcl-2 members, and suggest that their functional interdependence can be exploited therapeutically
Original languageEnglish
Pages (from-to)1958-1967
JournalCell death and differentiation
Issue number11
Publication statusPublished - 2007

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