Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel
Metrics: PDF 1446 views | HTML 2962 views | ?
Cody W. Lewis1,2,3, Zhigang Jin1,2,3, Dawn Macdonald1,2,3, Wenya Wei1, Xu Jing Qian1, Won Shik Choi1, Ruicen He1, Xuejun Sun1,2,3 and Gordon Chan1,2,3
1Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2
2Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2
3Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Alberta, Canada T6G 2J7
Keywords: cell cycle checkpoint, Wee1 kinase, paclitaxel, mitotic catastrophe, breast cancer
Received: October 21, 2016 Accepted: April 27, 2017 Published: May 13, 2017
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.