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

• Published in: Cell death & disease 2019-11, Vol.10 (11), p.837-15, Article 837
• Main Authors: Hope, Jacob M., Lopez-Cavestany, Maria, Wang, Wenjun, Reinhart-King, Cynthia A., King, Michael R.
• Format: Article
• Language: English
• Subjects: 13/2; 13/31; 13/95; 14/19; 38/89; 631/67/1059/602; 631/80/82/23; 96/95; Antibodies; Apoptosis; Bax protein; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Calcium influx; Calpain; Calpastatin; Cancer; Cell activation; Cell Biology; Cell Culture; Clinical trials; Computer applications; Cytotoxicity; Depolarization; Humans; Immunology; Intercellular Signaling Peptides and Proteins - pharmacology; Ion Channels - antagonists & inhibitors; Ion Channels - genetics; Ion Channels - metabolism; Life Sciences; Major outer membrane protein; Membrane permeability; Membrane potential; Mitochondria; Mitochondrial Membranes - metabolism; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; PC-3 Cells; Permeability; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrazines - pharmacology; Shear stress; Signal transduction; Spider Venoms - pharmacology; Thiadiazoles - pharmacology; TNF-Related Apoptosis-Inducing Ligand - pharmacology; X-Linked Inhibitor of Apoptosis Protein - metabolism; XIAP protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2063-6

TRAIL specifically induces apoptosis in cancer cells without affecting healthy cells. However, TRAIL’s cancer cytotoxicity was insufficient in clinical trials. Circulatory-shear stress is known to sensitize cancer cells to TRAIL. In this study, we examine the mechanism of this TRAIL sensitization with the goal of translating it to static conditions. GsMTx-4, a Piezo1 inhibitor, was found to reduce shear stress-related TRAIL sensitization, implicating Piezo1 activation as a potential TRAIL-sensitizer. The Piezo1 agonist Yoda1 recreated shear stress-induced TRAIL sensitization under static conditions. A significant increase in apoptosis occurred when PC3, COLO 205, or MDA-MB-231 cells were treated with Yoda1 and TRAIL in combination, but not in Bax-deficient DU145 cells. Calpastatin inhibited apoptosis in Yoda1-TRAIL treated cells, indicating that calpain activation is necessary for apoptosis by Yoda1 and TRAIL. Yoda1 and TRAIL treated PC3 cells showed increased mitochondrial outer membrane permeability (MOMP), mitochondrial depolarization, and activated Bax. This implies that Piezo1 activation sensitizes cancer cells to TRAIL through a calcium influx that activates calpains. The Calpains then induce MOMP by enhancing Bax activation. From these experiments a computational model was developed to simulate apoptosis for cells treated with TRAIL and increased calcium. The computational model elucidated the proapoptotic or antiapoptotic roles of Bax, Bcl-2, XIAP, and other proteins important in the mitochondrial-apoptotic signaling pathway.