Mechanosensitive nuclear uptake of chemotherapy
Nicholas R Scott1, Sowon Kang1, Sapun H Parekh1
1Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA.
Science Advances
|December 18, 2024
Summary
Nuclear-cytoskeletal coupling influences chemotherapy drug uptake. Modulating cell mechanics can sensitize or desensitize cancer nuclei to drugs like doxorubicin, offering new strategies against drug resistance.
Area of Science:
- Cell Biology
- Biophysics
- Cancer Therapeutics
Background:
- The cell nucleus is a key target for chemotherapy drugs.
- Nuclear-cytoskeletal coupling plays a role in cellular mechanics and drug transport.
- Understanding nuclear permeability is crucial for overcoming chemotherapy resistance.
Purpose of the Study:
- To investigate the relationship between nuclear-cytoskeletal coupling and the nuclear internalization of chemotherapy drugs.
- To determine how mechanical forces and cell strain affect drug uptake into the nucleus.
- To explore the potential of mechanical interventions to enhance chemotherapy efficacy.
Main Methods:
- Modulation of intracellular filaments and cell strain.
- Assessment of doxorubicin (DOX) nuclear influx in cancer cells.
- Analysis of nuclear permeability in extracted nuclei from various cancer cell lines.
- Evaluation of mechano-priming effects using paclitaxel.
Main Results:
- Acute changes in cell strain by disrupting filaments sensitize nuclei to DOX.
- Chronic reduction in cell strain desensitizes nuclei to DOX.
- Distinct nuclear permeability to DOX was observed across different invasive cancer cell lines.
- Mechano-priming with paclitaxel significantly enhanced DOX nuclear internalization.
Conclusions:
- Nuclear uptake of chemotherapy is a critical, unquantified factor in drug resistance.
- Nuclear permeability to chemotherapy can be tuned by modulating nuclear mechanotransduction.
- Mechano-priming presents a potential strategy to overcome chemotherapy drug resistance.
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