Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells.
Paclitaxel (PTX) is an antimitotic drug that possesses potent anticancer activity, but its therapeutic potential in the clinic has been hindered by drug resistance. Here, we report a mechanism by which cancer cells can exit from the PTX-induced mitotic arrest, i.e. mitotic slippage, and avoid subsequent death resulting in drug resistance. In cells experiencing mitotic slippage, Cdc6 protein level was significantly upregulated, Cdk1 activity was inhibited, and Cohesin/Rad21 was cleaved as a result. Cdc6 depletion by RNAi or Norcantharidin inhibited PTX-induced Cdc6 up-regulation, maintained Cdk1 activity, and repressed Cohesin/Rad21 cleavage. In all, this resulted in reduced mitotic slippage and reversal of PTX resistance. Moreover, in synchronized cells, the role of Cdc6 in mitotic exit under PTX pressure was also confirmed. This study indicates that Cdc6 may promote mitotic slippage by inactivation of Cdk1. Targeting of Cdc6 may serve as a promising strategy for enhancing the anticancer activity of PTX.
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Yue
Y
He
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Daoyu
D
Yan
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Dianpeng
D
Zheng
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Zhiming
Z
Hu
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Hongwei
H
Li
Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
Jinlong
J
Li
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel; D034741:RNA, Small Interfering / Q000235:genetics
C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel