Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest.
Mattia Pavani1, Elena Chiroli1, Camilla Cancrini1
1IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy.
Cell Reports
|March 14, 2023
Summary
A small fraction of human cells escape prolonged mitotic arrest induced by nocodazole, showing reduced DNA damage. Triap1 upregulation in surviving cells promotes resistance by retaining cytochrome c, opposing apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Microtubule-targeting drugs induce mitotic arrest, followed by G1 arrest, crucial for their efficacy.
- Understanding mechanisms of resistance to these cell cycle arrest drugs is vital for effective cancer therapy.
Purpose of the Study:
- To investigate the long-term fate of human cells arrested by nocodazole.
- To identify molecular factors contributing to resistance against prolonged mitotic arrest.
Main Methods:
- Long-term culture of human cells treated with nocodazole.
- Analysis of DNA damage, p21 activation, and apoptotic markers.
- Assessment of Triap1 protein levels and its role in cell survival and apoptosis.
Main Results:
- A subset of G1-arrested cells escaped arrest and resumed proliferation with less DNA damage and p21 activation.
- Surviving cells exhibited increased levels of the anti-apoptotic protein Triap1.
- Triap1 upregulation protected cells by retaining cytochrome c in mitochondria, inhibiting caspase activation.
Conclusions:
- Triap1 upregulation is a key mechanism conferring resistance to nocodazole-induced prolonged mitotic arrest.
- Targeting Triap1 could potentially re-sensitize resistant cells to microtubule-targeting agents.
- This study reveals a novel pathway for acquired resistance to chemotherapy.
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