title: APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction.
abstract: Anaphase-promoting complex Cdc20 (APC(Cdc20)) plays pivotal roles in governing mitotic progression. By suppressing APC(Cdc20), antimitotic agents activate the spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APC(Cdc20) target, such that depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in a small interfering RNA screen that, upon knockdown, sensitizes otherwise resistant cancer cells to chemoradiation in a Bim-dependent manner. Consistently, human adult T cell leukemia cells that acquire elevated APC(Cdc20) activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APC(Cdc20) in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Mingjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Chongqing Road, Shanghai 200025, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institute of Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.affiliation: Thoracic Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D050256:Antimitotic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D064199:Cdc20 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D059248:Chemoradiotherapy; D016356:Gene Products, tax / Q000096:biosynthesis; D045325:HCT116 Cells; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D008941:Spindle Apparatus / Q000235:genetics; D054875:Ubiquitination
chemical_list: D050256:Antimitotic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D064199:Cdc20 Proteins; D016356:Gene Products, tax; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C577488:CDC20 protein, human