TY - JOUR
T1 - Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly
AU - Huang, Hsiao Chun
AU - Shi, Jue
AU - Orth, James D.
AU - Mitchison, Timothy J.
N1 - Funding Information:
We thank Andrew Murray, Bin Zheng, and the Mitchison lab for helpful discussions; Peter Sorger, Jagesh Shah, Randy King, and Paul Chang for reagents and suggestions; Rebecca Ward for critical reading of the manuscript; and Jennifer Waters and Lara Petrak in Nikon Imaging Center (HMS) for imaging assistance. This work was supported by NCI CA078048. EMD534085 was supplied by Merck Serono.
PY - 2009/10/6
Y1 - 2009/10/6
N2 - 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.
AB - 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=70349452101&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2009.08.020
DO - 10.1016/j.ccr.2009.08.020
M3 - Journal article
C2 - 19800579
AN - SCOPUS:70349452101
SN - 1535-6108
VL - 16
SP - 347
EP - 358
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
