Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells

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 subseq...

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Main Authors: He, Yue, Yan, Daoyu, Zheng, Dianpeng, Hu, Zhiming, Li, Hongwei, Li, Jinlong
Format: Online
Language:English
Published: Public Library of Science 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017606/
id pubmed-5017606
recordtype oai_dc
spelling pubmed-50176062016-09-27 Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells He, Yue Yan, Daoyu Zheng, Dianpeng Hu, Zhiming Li, Hongwei Li, Jinlong Research Article 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. Public Library of Science 2016-09-09 /pmc/articles/PMC5017606/ /pubmed/27611665 http://dx.doi.org/10.1371/journal.pone.0162633 Text en © 2016 He et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author He, Yue
Yan, Daoyu
Zheng, Dianpeng
Hu, Zhiming
Li, Hongwei
Li, Jinlong
spellingShingle He, Yue
Yan, Daoyu
Zheng, Dianpeng
Hu, Zhiming
Li, Hongwei
Li, Jinlong
Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
author_facet He, Yue
Yan, Daoyu
Zheng, Dianpeng
Hu, Zhiming
Li, Hongwei
Li, Jinlong
author_sort He, Yue
title Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
title_short Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
title_full Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
title_fullStr Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
title_full_unstemmed Cell Division Cycle 6 Promotes Mitotic Slippage and Contributes to Drug Resistance in Paclitaxel-Treated Cancer Cells
title_sort cell division cycle 6 promotes mitotic slippage and contributes to drug resistance in paclitaxel-treated cancer cells
description 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.
publisher Public Library of Science
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017606/
_version_ 1613647732279345152

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