The Role of the APC/C and Its Coactivators Cdh1 and Cdc20 in Cancer Development and Therapy

Abstract

To sustain genomic stability by correct DNA replication and mitosis, cell cycle progression is tightly controlled by the cyclic activity of cyclin-dependent kinases, their binding to cyclins in the respective phase and the regulation of cyclin levels by ubiquitin-dependent proteolysis. The spindle assembly checkpoint plays an important role at the metaphase-anaphase transition to ensure a correct separation of sister chromatids before cytokinesis and to initiate mitotic exit, as an incorrect chromosome distribution may lead to genetically unstable cells and tumorigenesis. The ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C) is essential for these processes by mediating the proteasomal destruction of cyclins and other important cell cycle regulators. To this end, it interacts with the two regulatory subunits Cdh1 and Cdc20. Both play a role in tumorigenesis with Cdh1 being a tumor suppressor and Cdc20 an oncogene. In this review, we summarize the current knowledge about the APC/C-regulators Cdh1 and Cdc20 in tumorigenesis and potential targeted therapeutic approaches.

Keywords: APC/C; Cdh1; antimitotic therapy; mitotic exit; mitotic slippage; spindle assembly checkpoint.

FIGURE 1

The role of APC/C in cell cycle regulation. The transition between the cell cycle phases is regulated by the cyclic activity of cyclin-Cdk complexes. In mitotic entry, cyclin B-Cdk1 plays a crucial role. In early prometaphase, chromosomes bind to the mitotic spindle and improperly connected kinetochores lead to SAC-activation. At first, this partially inhibits substrate recruitment of APC/C activated via Cdc20, but various prometaphase proteins such as cyclin A can be further marked for degradation by SAC-APC/C^Cdc20. After correct attachment of all chromosomes to the mitotic spindle, the SAC is inactivated, leading to degradation of additional proteins such as cyclin B and securin via APC/C^Cdc20 in metaphase, mediating chromosome segregation and initiating mitotic exit. Cyclin B-degradation leads to Cdk1 inhibition, resulting in dephosphorylation and activation of Cdh1. APC/C^Cdh1 then initiates the degradation of various proteins during ana- and telophase such as Cdc20, Plk1, and Aurora A/B. At the end of mitosis, APC/C^Cdh1 inactivates APC/C^Cdc20 and regulates anaphase spindle dynamics and cytokinesis. APC/C^Cdh1 is thus activated from late mitosis and controls the decision between proliferation and differentiation in G1-phase. In G2-phase, APC/C^Cdh1 can be activated in response to DNA-damage to prevent mitotic entry and allow DNA-repair.SAC, spindle assembly checkpoint; APC/C, anaphase promoting complex; Plk, Polo-like Kinase; Cdk, cyclin-dependent kinase.

FIGURE 2

Cancer treatment targeting the APC/C. Due to disturbed microtubule kinetics after spindle poison treatment with resulting defective chromosome attachment and free kinetochores, the SAC cannot be satisfied and the MCC is formed. After binding to Mad2, BubR1, and Bub3 in the MCC Cdc20 can no longer activate the APC/C. APC/C inhibition leads to stabilization of securin and cyclin B, preventing chromosome segregation and mitotic exit. Prolonged mitotic arrest triggers Mcl-1-degradation, thus caspase activation and apoptosis in mitosis. SAC-deficient malignant cells may survive treatment with spindle poisons due to residual APC/C activity and slow cyclin B-degradation. Inhibition of APC/C or the proteasome can prevent this mitotic slippage, consolidate the mitotic block and enhance the antitumor effect. Mcl-1 inhibition may additionally promote apoptosis. SAC, spindle assembly checkpoint; MCC, mitotic checkpoint complex; APC/C, anaphase promoting complex.