Enhanced tumor cell killing by ultrasound after microtubule depolymerization

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.