Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL-Mediated Apoptosis

Area of Science:

• Oncology
• Biophysics
• Biomedical Engineering

Background:

• Non-surgical prostate cancer (PCa) therapies are needed.
• Soluble tumor necrosis factor (TNF-α) related apoptosis inducing ligand (TRAIL) has preclinical efficacy but a short half-life.
• Fluid shear stress activates mechanosensitive ion channels (MSCs) like Piezo1, enhancing TRAIL-induced apoptosis.

Purpose of the Study:

• To investigate the use of noninvasive focal ultrasound (FUS) to enhance TRAIL-mediated apoptosis in PCa.
• To explore the role of Piezo1 and MSCs in FUS-augmented TRAIL therapy.

Main Methods:

• Thermally safe FUS parameters were applied to PCa cells and in vivo models.
• Mechanisms investigated via calcium chelation, MSC inhibitors, and PIEZO knockdown.
• In vivo studies involved multi-dose FUS exposure and assessment of tumor burden and apoptosis markers.

Main Results:

• TRAIL sensitivity increased with higher FUS pressure in PCa cells, mediated by Piezo1.
• FUS significantly reduced tumor burden in vivo when applied at 0 and 4-h intervals after TRAIL.
• Increased apoptosis was confirmed by enhanced cleaved-caspase 3 expression.

Conclusions:

• FUS can noninvasively augment TRAIL therapy for prostate cancer by activating Piezo1.
• This mechanotherapy approach is clinically translatable and may apply to other cancer types.