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Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel

Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-ca...

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Autores principales: Lewis, Cody W., Jin, Zhigang, Macdonald, Dawn, Wei, Wenya, Qian, Xu Jing, Choi, Won Shik, He, Ruicen, Sun, Xuejun, Chan, Gordon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650293/
https://www.ncbi.nlm.nih.gov/pubmed/29088738
http://dx.doi.org/10.18632/oncotarget.17848
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author Lewis, Cody W.
Jin, Zhigang
Macdonald, Dawn
Wei, Wenya
Qian, Xu Jing
Choi, Won Shik
He, Ruicen
Sun, Xuejun
Chan, Gordon
author_facet Lewis, Cody W.
Jin, Zhigang
Macdonald, Dawn
Wei, Wenya
Qian, Xu Jing
Choi, Won Shik
He, Ruicen
Sun, Xuejun
Chan, Gordon
author_sort Lewis, Cody W.
collection PubMed
description Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-cancer drugs. MK-1775 promotes cancer cells to bypass the cell-cycle checkpoints and prematurely enter mitosis. In our study, we show premature mitotic cells that arise from MK-1775 treatment exhibited centromere fragmentation, a morphological feature of mitotic catastrophe that is characterized by centromeres and kinetochore proteins that co-cluster away from the condensed chromosomes. In addition to stimulating early mitotic entry, MK-1775 treatment also delayed mitotic exit. Specifically, cells treated with MK-1775 following release from G1/S or prometaphase arrested in mitosis. MK-1775 induced arrest occurred at metaphase and thus, cells required 12 times longer to transition into anaphase compared to controls. Consistent with an arrest in mitosis, MK-1775 treated prometaphase cells maintained high cyclin B1 and low phospho-tyrosine 15 Cdk1. Importantly, MK-1775 induced mitotic arrest resulted in cell death regardless the of cell-cycle phase prior to treatment suggesting that Wee1 inhibitors are also anti-mitotic agents. We found that paclitaxel enhances MK-1775 mediated cell killing. HeLa and different breast cancer cell lines (T-47D, MCF7, MDA-MB-468 and MDA-MB-231) treated with different concentrations of MK-1775 and low dose paclitaxel exhibited reduced cell survival compared to mono-treatments. Our data highlight a new potential strategy for enhancing MK-1775 mediated cell killing in breast cancer cells.
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spelling pubmed-56502932017-10-30 Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel Lewis, Cody W. Jin, Zhigang Macdonald, Dawn Wei, Wenya Qian, Xu Jing Choi, Won Shik He, Ruicen Sun, Xuejun Chan, Gordon Oncotarget Research Paper Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-cancer drugs. MK-1775 promotes cancer cells to bypass the cell-cycle checkpoints and prematurely enter mitosis. In our study, we show premature mitotic cells that arise from MK-1775 treatment exhibited centromere fragmentation, a morphological feature of mitotic catastrophe that is characterized by centromeres and kinetochore proteins that co-cluster away from the condensed chromosomes. In addition to stimulating early mitotic entry, MK-1775 treatment also delayed mitotic exit. Specifically, cells treated with MK-1775 following release from G1/S or prometaphase arrested in mitosis. MK-1775 induced arrest occurred at metaphase and thus, cells required 12 times longer to transition into anaphase compared to controls. Consistent with an arrest in mitosis, MK-1775 treated prometaphase cells maintained high cyclin B1 and low phospho-tyrosine 15 Cdk1. Importantly, MK-1775 induced mitotic arrest resulted in cell death regardless the of cell-cycle phase prior to treatment suggesting that Wee1 inhibitors are also anti-mitotic agents. We found that paclitaxel enhances MK-1775 mediated cell killing. HeLa and different breast cancer cell lines (T-47D, MCF7, MDA-MB-468 and MDA-MB-231) treated with different concentrations of MK-1775 and low dose paclitaxel exhibited reduced cell survival compared to mono-treatments. Our data highlight a new potential strategy for enhancing MK-1775 mediated cell killing in breast cancer cells. Impact Journals LLC 2017-05-13 /pmc/articles/PMC5650293/ /pubmed/29088738 http://dx.doi.org/10.18632/oncotarget.17848 Text en Copyright: © 2017 Lewis et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Lewis, Cody W.
Jin, Zhigang
Macdonald, Dawn
Wei, Wenya
Qian, Xu Jing
Choi, Won Shik
He, Ruicen
Sun, Xuejun
Chan, Gordon
Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title_full Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title_fullStr Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title_full_unstemmed Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title_short Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
title_sort prolonged mitotic arrest induced by wee1 inhibition sensitizes breast cancer cells to paclitaxel
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650293/
https://www.ncbi.nlm.nih.gov/pubmed/29088738
http://dx.doi.org/10.18632/oncotarget.17848
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