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Mitotic checkpoint defects in human cancers and their implications to chemotherapy
Xianghong Wang1, Hiu Wing Cheung, Abel C S Chun
1Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong. xhwang@hkucc.hku.hk
Abstract:
The mitotic checkpoint, also known as spindle assembly checkpoint, is to ensure accurate chromosome segregation by inducing mitotic arrest when errors occur in the spindle structure or in the alignment of the chromosomes on the spindle. Loss of mitotic checkpoint control is a common event in human cancer cells, which is thought to be responsible for chromosome instability frequently observed in cancer cells. Several reports have shown that cells with a defective mitotic checkpoint are more resistant to several types of anticancer drugs from microtubule disruptors to DNA damaging agents. In addition, inactivation of key mitotic checkpoint proteins such as BUB (budding uninhibited by benzimidazole) and MAD (mitotic arrest deficient ) is influential in drug resistance in mitotic checkpoint defective cancer cells. The mitotic checkpoint has also been linked to DNA damage response and a defective mitotic checkpoint confers cancer cells resistance to certain DNA damaging anticancer drugs. This review presents recent evidence on mitotic checkpoint defects in human cancers and their association with resistance to anticancer drugs. In addition, the clinical importance and potential therapeutic implications of targeting the mitotic checkpoint to reverse drug resistance in cancer cells are also discussed.
Insights
Defects in the mitotic checkpoint (spindle assembly checkpoint) are common in human cancers, leading to chromosome instability and resistance to anticancer drugs. Targeting this checkpoint may reverse drug resistance in cancer cells.
Area of Science:
- Cell Biology
- Cancer Biology
- Genetics
Background:
- The mitotic checkpoint ensures accurate chromosome segregation during cell division.
- Loss of mitotic checkpoint control is frequent in human cancers, contributing to chromosome instability.
- Defective mitotic checkpoints are linked to cancer cell resistance to various anticancer drugs.
Purpose of the Study:
- To review recent evidence on mitotic checkpoint defects in human cancers.
- To explore the association between these defects and anticancer drug resistance.
- To discuss the clinical importance and therapeutic potential of targeting the mitotic checkpoint.
Main Methods:
- Literature review of recent studies on mitotic checkpoints in cancer.
- Analysis of the relationship between mitotic checkpoint proteins (BUB, MAD) and drug resistance.
- Examination of the link between mitotic checkpoint function and DNA damage response.
Main Results:
- Mitotic checkpoint defects are prevalent in human cancers and drive chromosome instability.
- Inactivation of key mitotic checkpoint proteins (BUB, MAD) confers resistance to microtubule disruptors and DNA damaging agents.
- A defective mitotic checkpoint enhances cancer cell resistance to certain DNA damaging anticancer drugs.
Conclusions:
- Mitotic checkpoint defects are a significant factor in cancer development and drug resistance.
- Targeting the mitotic checkpoint presents a potential therapeutic strategy to overcome drug resistance in cancer.
- Further research into the clinical implications of targeting the mitotic checkpoint is warranted.
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