M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s

Li, Jianquan, Dang, Nanmao, Martinez-Lopez, Nuria, Jowsey, Paul, Huang, Dong, Lightowlers, Robert N., Gao, Fei and Huang, Jun-Yong (2019) M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s. Cell Division, 14 (1). ISSN 1747-1028

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Official URL: https://doi.org/10.1186/s13008-019-0049-5

Abstract

Background
Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC).

Results
We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family.

Conclusion
Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent.

Item Type: Article
Uncontrolled Keywords: M2I-1, Cyclin B1, MCL-1, Nocodazole, Apoptosis, Taxol
Subjects: C100 Biology
C400 Genetics
C900 Others in Biological Sciences
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 20 May 2020 09:07
Last Modified: 20 May 2020 09:15
URI: http://nrl.northumbria.ac.uk/id/eprint/43210

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