Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage

Xing Zeng, Frederic Sigoillot, Shantanu Gaur, Sungwoon Choi, Kathleen L. Pfaff, Dong-Chan Oh, Nathaniel Hathaway, Nevena Dimova, Gregory D. Cuny, Randall W. King, Xing Zeng, Frederic Sigoillot, Shantanu Gaur, Sungwoon Choi, Kathleen L. Pfaff, Dong-Chan Oh, Nathaniel Hathaway, Nevena Dimova, Gregory D. Cuny, Randall W. King

Index: Cancer Cell 18 , 382-95, (2010)

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Abstract

Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest.