Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly.
Current antimitotics work by perturbing spindle assembly, which activates the spindle assembly checkpoint, causes mitotic arrest, and triggers apoptosis. Cancer cells can resist such killing by premature exit, before cells initiate apoptosis, due to a weak checkpoint or rapid slippage. We reasoned blocking mitotic exit downstream of the checkpoint might circumvent this resistance. Using single-cell approaches, we showed that blocking mitotic exit by Cdc20 knockdown slowed cyclin B1 proteolysis, thus allowed more time for death initiation. Killing by Cdc20 knockdown did not require checkpoint activity and can occur by intrinsic apoptosis or an alternative death pathway when Bcl2 was overexpressed. We conclude targeting Cdc20, or otherwise blocking mitotic exit, may be a better cancer therapeutic strategy than perturbing spindle assembly.
Huang
Hsiao-Chun
HC
Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA. hsiao-chun_huang@hms.harvard.edu
Shi
Jue
J
Orth
James D
JD
Mitchison
Timothy J
TJ
D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D010539:Permeability; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D050256:Antimitotic Agents; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D064199:Cdc20 Proteins; C577491:Cdc20 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C577488:CDC20 protein, human; D016547:Kinesins; D017239:Paclitaxel