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
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 bee...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Cell Division |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13008-019-0049-5 |
| _version_ | 1819067022511702016 |
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| author | Jianquan Li Nanmao Dang Nuria Martinez-Lopez Paul A. Jowsey Dong Huang Robert N. Lightowlers Fei Gao Jun-Yong Huang |
| author_facet | Jianquan Li Nanmao Dang Nuria Martinez-Lopez Paul A. Jowsey Dong Huang Robert N. Lightowlers Fei Gao Jun-Yong Huang |
| author_sort | Jianquan Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T16:11:39Z |
| format | Article |
| id | doaj.art-a16ed0bf513c447d9b4284c3f91e72d5 |
| institution | Directory Open Access Journal |
| issn | 1747-1028 |
| language | English |
| last_indexed | 2024-12-21T16:11:39Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Division |
| spelling | doaj.art-a16ed0bf513c447d9b4284c3f91e72d52022-12-21T18:57:47ZengBMCCell Division1747-10282019-06-0114111510.1186/s13008-019-0049-5M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1sJianquan Li0Nanmao Dang1Nuria Martinez-Lopez2Paul A. Jowsey3Dong Huang4Robert N. Lightowlers5Fei Gao6Jun-Yong Huang7Institute for Cell and Molecular Biosciences, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityMedical Toxicology Centre, Institute of Cellular Medicine, NIHR Health Protection Research Unit, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityInstitute for Cell and Molecular Biosciences, Newcastle UniversityAbstract 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.http://link.springer.com/article/10.1186/s13008-019-0049-5M2I-1Cyclin B1MCL-1NocodazoleTaxolApoptosis |
| spellingShingle | Jianquan Li Nanmao Dang Nuria Martinez-Lopez Paul A. Jowsey Dong Huang Robert N. Lightowlers Fei Gao Jun-Yong Huang 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 M2I-1 Cyclin B1 MCL-1 Nocodazole Taxol Apoptosis |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | M2I-1 Cyclin B1 MCL-1 Nocodazole Taxol Apoptosis |
| url | http://link.springer.com/article/10.1186/s13008-019-0049-5 |
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