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Activation of Piezo1 sensitizes cells to TRAIL-mediated apoptosis through mitochondrial outer membrane permeability

Jacob M Hope1, Maria Lopez-Cavestany1, Wenjun Wang1

  • 1Department of Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, Nashville, TN, 37235, USA.

Cell Death & Disease
|November 6, 2019
PubMed

Insights

This study reveals that activating Piezo1 channels with Yoda1 sensitizes cancer cells to TRAIL-induced apoptosis by increasing intracellular calcium, activating calpains, and promoting mitochondrial outer membrane permeabilization. This mechanism enhances TRAIL

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biophysics

Background:

  • TRAIL (TNF-related apoptosis-inducing ligand) selectively induces apoptosis in cancer cells.
  • Clinical efficacy of TRAIL is limited due to insufficient cytotoxicity.
  • Shear stress sensitizes cancer cells to TRAIL, suggesting a mechanotransduction pathway.

Purpose of the Study:

  • To elucidate the mechanism of shear stress-induced TRAIL sensitization.
  • To translate shear stress findings to static conditions for therapeutic application.
  • To identify key molecular players in TRAIL sensitization.

Main Methods:

  • Utilized Piezo1 inhibitor GsMTx-4 and agonist Yoda1 to study mechanosensitive channel involvement.
  • Assessed apoptosis induction in various cancer cell lines (PC3, COLO 205, MDA-MB-231, DU145) with Yoda1 and TRAIL.
  • Investigated the role of calpain activation using calpastatin.
  • Analyzed mitochondrial outer membrane permeability (MOMP), mitochondrial depolarization, and Bax activation.
  • Developed a computational model to simulate apoptosis signaling pathways.

Main Results:

  • Piezo1 activation by Yoda1 mimicked shear stress-induced TRAIL sensitization under static conditions.
  • Yoda1 and TRAIL combination significantly increased apoptosis in sensitive cell lines but not in Bax-deficient cells.
  • Calpastatin treatment inhibited Yoda1-TRAIL-induced apoptosis, confirming calpain necessity.
  • Yoda1 and TRAIL treatment led to increased MOMP, mitochondrial depolarization, and Bax activation.
  • Computational modeling provided insights into the roles of Bax, Bcl-2, and XIAP in apoptosis.

Conclusions:

  • Piezo1 activation sensitizes cancer cells to TRAIL via a calcium influx-dependent pathway.
  • Calpain activation downstream of Piezo1 is crucial for TRAIL sensitization.
  • Calpains enhance TRAIL-induced apoptosis by promoting Bax activation and MOMP.
  • Findings offer a potential strategy to enhance TRAIL-based cancer therapy.

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