Abstract
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.
Highlights
Microtubule has been a major target for the anticancer drugs development
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
Mitotic slippage contributes to drug resistance in PTX-treated HepG2 cells
Summary
Microtubule has been a major target for the anticancer drugs development. The great success of PTX made it as an ‘epoch-making’ anticancer drug. PTX is currently one of the most widely used drugs for variously cancer chemotherapy [1]. PTX possess potent anticancer activity, it has been shown that treatment with this drug often results in resistance as well as undesirable side effects. Acquired resistance to this drug has become one of the major therapeutic obstacles. Mechanism clarification and possible strategies to overcome PTX resistance holds significant purpose [2]
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