Cdc20 turnover rate: A key determinant in cancer patient response to anti-mitotic therapies?


Many current cancer therapies target mitosis. They do so by perturbing mitotic spindle formation and causing prolonged activation of the spindle assembly checkpoint (SAC). Whilst this leads to mitotic arrest, it does not always lead to cell death. In fact, cells exhibit a heterogeneous response to anti-mitotic drugs, that is to say that whilst some cells die in mitosis, others exit or “slip” out of mitosis into interphase where they may survive and continue to divide. This is not due to genetic variation as different outcomes are observed between isogenic offspring of individual cells. Understanding the mechanistic basis for this behavior could have a major impact on predicting patient response to anti-mitotic agents, such as the taxanes and vinca alkaloids.

Whether cells die in mitosis or undergo mitotic slippage is determined by at least two competing processes: induction of apoptotic pathways that promote death in mitosis, and degradation of cyclin B that promotes mitotic slippage. Stochastic variation in the rates of these two processes in different cells, and potentially the thresholds at which these trigger death or slippage, would provide an explanation for the heterogeneous response. In a recent BioEssays review, Nilsson [1] proposed that a key factor in establishing these rates is the abundance of Cdc20. Cdc20 is a co-activator of the APC/C, the ubiquitin ligase that is the target of the SAC. The APC/C induces degradation of securin to trigger sister chromatid separation and cyclin B to drive mitotic exit. Some anti-apoptotic proteins, including Mcl-1, are also targets of APC/CCdc20 and so Cdc20 expression can contribute to the rates of both death in mitosis and mitotic slippage.

Paradoxically, Cdc20 itself is degraded by the APC/C. This should reinforce the SAC by preventing mitotic progression when spindles are not properly assembled. However, it is not this straightforward, as Cdc20 is also part of the mitotic checkpoint complex (MCC). This inhibitory complex, which also includes Mad2, BubR1, and Bub3, assembles at unattached kinetochores before binding the APC/C and preventing substrate degradation. Hence, destruction of Cdc20 also promotes mitotic exit by enabling MCC disassembly. Cdc20 therefore has multiple and, in part, opposing functions in mitosis: it promotes SAC-mediated mitotic arrest through the MCC, induces apoptosis through degradation of anti-apoptotic proteins and triggers mitotic exit through cyclin B degradation. As a consequence, the turnover rate of Cdc20, rather than simply its abundance, has a substantial impact on whether cells die in mitosis or undergo slippage in response to mitotic arrest.

Intriguingly, the mechanism of Cdc20 turnover is different depending on whether it is free or bound up in the MCC. Recent studies reveal that the Apc15 subunit of the APC/C is required to degrade MCC-bound Cdc20, but not free Cdc20, whilst Apc15 is not required for degradation of other APC/C substrates, such as securin or cyclin B [2-4]. This suggests the presence of different Cdc20 pools with different turnover rates, one promoting mitotic arrest through the MCC and one promoting mitotic exit (and apoptosis) through substrate degradation. If this model holds true, then it will be key to identify mechanisms that regulate Cdc20 turnover rates; for example, why does Apc15 contribute to one and not the other, and what other post-translational mechanisms may be involved? Also does this contribute to the non-genetic heterogeneity in the rates of cyclin B loss and accumulation of apoptotic signals? Answers to these questions will help to predict the response of cancer patients to traditional and targeted anti-mitotic therapies, as well as revealing new approaches to targeting mitotic exit.


The author is grateful to The Wellcome Trust and the Association for International Cancer Research for funding research in his laboratory.