Abstract
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.
Highlights
Introduction With8 million cancer-related deaths per year, major breakthroughs in cancer therapy are needed[1]
We demonstrate the role of Piezo[1] in shear stress-induced TRAIL sensitization of cancer cells, translate Piezo1’s TRAIL-sensitizing role to static conditions using Yoda[1], and explore the mechanism of Piezo[1] and TRAIL’s apoptotic synergy using Yoda[1] experiments and a new computational model
Shear sensitization of PC3 cells to TRAIL-mediated apoptosis is reduced by mechanosensitive ion channels (MSCs) inhibition Cell viability was measured after PC3 cells were treated with 250 ng/mL TRAIL, shear stress of 2.0 dyn/cm[2], and 10 μM GsMTx-4 for 4 h (Fig. 1a)
Summary
8 million cancer-related deaths per year, major breakthroughs in cancer therapy are needed[1]. Tumornecrosis-factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapy discovered by Wiley et al in 19952. TRAIL induces apoptosis in cancer cells, while sparing healthy cells minimizing side effects[3]. This prompted multiple clinical trials using TRAIL4–7. The clinical trials showed that TRAIL lacked the necessary cytotoxicity for clinical relevance. Focus has shifted to discovering compounds that enhance TRAIL’s cytotoxicity while maintaining its specificity[8]
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