Journal
CANCER SCIENCE
Volume 112, Issue 9, Pages 3711-3721Publisher
WILEY
DOI: 10.1111/cas.15018
Keywords
anticancer drug resistance; apoptosis; CHAMP1; Mcl-1; mitotic cell death
Categories
Funding
- JSPS KAKENHI [24370078, 24650616, 19K22410, 20K16295]
- MEXT KAKENHI [26116501, 16H01296]
- P-DIRECT from AMED
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [24650616, 26116501, 19K22410, 20K16295, 16H01296] Funding Source: KAKEN
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Depletion of the mitotic regulator CHAMP1 accelerates mitotic cell death and reduces mitotic slippage, leading to decreased resistance to antimitotic drugs. CHAMP1 plays a role in maintaining Mcl-1 expression, suggesting it can be a target to overcome drug resistance in mitotic cells.
Antimitotic drugs such as vinca alkaloids and taxanes cause mitotic cell death after prolonged mitotic arrest. However, a fraction of cells escape from mitotic arrest by undergoing mitotic slippage, which is related to resistance to antimitotic drugs. Tipping the balance to mitotic cell death thus can be a way to overcome the drug resistance. Here we found that depletion of a mitotic regulator, CHAMP1 (chromosome alignment-maintaining phosphoprotein, CAMP), accelerates the timing of mitotic cell death after mitotic arrest. Live cell imaging revealed that CHAMP1-depleted cells died earlier than mock-treated cells in the presence of antimitotic drugs that resulted in the reduction of cells undergoing mitotic slippage. Depletion CHAMP1 reduces the expression of antiapoptotic Bcl-2 family proteins, especially Mcl-1. We found that CHAMP1 maintains Mcl-1 expression both at protein and mRNA levels independently of the cell cycle. At the protein level, CHAMP1 maintains Mcl-1 stability by suppressing proteasome-dependent degradation. Depletion of CHAMP1 reduces cell viability, and exhibits synergistic effects with antimitotic drugs. Our data suggest that CHAMP1 plays a role in the maintenance of Mcl-1 expression, implying that CHAMP1 can be a target to overcome the resistance to antimitotic drugs.
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