AI Article Synopsis
- Drugs targeting microtubules, like nocodazole, cause a prolonged mitotic arrest in cells, eventually leading to a G1 arrest.
- A small percentage of G1-arrested cells manage to escape this arrest and continue to proliferate, exhibiting lower DNA damage and p21 activation.
- Increased levels of the anti-apoptotic protein Triap1 help these cells survive nocodazole treatment, suggesting that Triap1 plays a critical role in developing resistance to drugs that induce prolonged mitotic arrest.
Article Abstract
Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes proliferation. These escaping cells experience reduced DNA damage and p21 activation. Cells surviving treatment are enriched for anti-apoptotic proteins, including Triap1. Increasing Triap1 levels allows cells to survive the first treatment with reduced DNA damage and lower levels of p21; accordingly, decreasing Triap1 re-sensitizes cells to nocodazole. We show that Triap1 upregulation leads to the retention of cytochrome c in the mitochondria, opposing the partial activation of caspases caused by nocodazole. In summary, our results point to a potential role of Triap1 upregulation in the emergence of resistance to drugs that induce prolonged mitotic arrest.
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| http://dx.doi.org/10.1016/j.celrep.2023.112215 | DOI Listing |
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