Enhanced tumor cell killing by ultrasound after microtubule depolymerization
Aditi Singh1,2, Ajay Tijore1, Felix Margadant1
1Mechanobiology Institute National University of Singapore Singapore.
Abstract:
Recent studies show that tumor cells are vulnerable to mechanical stresses and undergo calcium-dependent apoptosis (mechanoptosis) with mechanical perturbation by low-frequency ultrasound alone. To determine if tumor cells are particularly sensitive to mechanical stress in certain phases of the cell cycle, inhibitors of the cell-cycle phases are tested for effects on mechanoptosis. Most inhibitors show no significant effect, but inhibitors of mitosis that cause microtubule depolymerization increase the mechanoptosis. Surprisingly, ultrasound treatment also disrupts microtubules independent of inhibitors in tumor cells but not in normal cells. Ultrasound causes calcium entry through mechanosensitive Piezo1 channels that disrupts microtubules via calpain protease activation. Myosin IIA contractility is required for ultrasound-mediated mechanoptosis and microtubule disruption enhances myosin IIA contractility through activation of GEF-H1 and RhoA pathway. Further, ultrasound promotes contractility-dependent Piezo1 expression and localization to the peripheral adhesions where activated Piezo1 allows calcium entry to continue feedback loop. Thus, the synergistic action of ultrasound and nanomolar concentrations of microtubule depolymerizing agents can enhance tumor therapies.
Insights
Low-frequency ultrasound induces cancer cell death (mechanoptosis) by disrupting microtubules and activating calcium channels. Combining ultrasound with microtubule-disrupting agents enhances this effect for potential tumor therapies.
Area of Science:
- Biophysics
- Cell Biology
- Cancer Research
Background:
- Tumor cells exhibit vulnerability to mechanical stress.
- Mechanical stress can induce calcium-dependent apoptosis, termed mechanoptosis.
- Low-frequency ultrasound alone can trigger mechanoptosis in tumor cells.
Purpose of the Study:
- To investigate the cell-cycle phase sensitivity of tumor cells to mechanical stress.
- To identify mechanisms underlying ultrasound-induced mechanoptosis.
- To explore synergistic therapeutic strategies combining ultrasound and cell-cycle inhibitors.
Main Methods:
- Utilized cell-cycle phase inhibitors to assess mechanoptosis sensitivity.
- Investigated the role of microtubules and calcium channels (Piezo1) in ultrasound-induced mechanoptosis.
- Examined the involvement of calpain protease, Myosin IIA, GEF-H1, and RhoA pathways.
Main Results:
- Mitotic inhibitors that depolymerize microtubules significantly increased mechanoptosis.
- Ultrasound treatment disrupted microtubules in tumor cells, but not normal cells.
- Ultrasound-induced calcium entry via Piezo1 channels, calpain activation, and Myosin IIA contractility were crucial for mechanoptosis.
- Microtubule disruption enhanced Myosin IIA contractility, promoting Piezo1 expression and activity.
Conclusions:
- Tumor cells are sensitive to mechanical stress, particularly when microtubules are disrupted.
- Ultrasound disrupts microtubules and triggers a calcium-dependent apoptotic pathway involving Piezo1 and Myosin IIA.
- Synergistic application of ultrasound and microtubule-disrupting agents shows promise for enhancing cancer therapies.
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