Editors' ChoiceCancer

A new hope? Yoda1 uses the “force” to sensitize cancer cells to TRAIL-mediated apoptosis

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Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaaz9752
DOI: 10.1126/scitranslmed.aaz9752


A mechanosensitive ion channel agonist mimics shear stress to enhance the cytotoxic effects of TRAIL on cancer cells.

Since its discovery in 1995, tumor necrosis factor–α–related apoptosis-inducing ligand (TRAIL) has generated great interest as a cancer therapy due to its cancer-specific apoptosis induction, which raised the hope of a cancer therapy with minimal off-target effects. Unfortunately, a rash of clinical trials revealed that TRAIL lacked sufficient cytotoxicity to demonstrate clinical significance. Recent efforts have focused on developing methods to enhance TRAIL cytotoxicity while maintaining its cancer specificity. In one of these methods, researchers demonstrated that circulatory shear stress can sensitize cancer cells to TRAIL-mediated apoptosis, though a potential mechanism has not been established and a means of exploiting this pathway has not yet been identified.

A new study published in Cell Death & Disease may have gotten us a little bit closer. Hope and colleagues elucidate the mechanism for shear stress sensitization to TRAIL, demonstrating that mechanosensitive ion channel Piezo1 plays a role in TRAIL-mediated apoptosis. They show that a small molecule Piezo1 agonist, Yoda1, can translate Piezo1’s TRAIL sensitization to static conditions in several cancer cell lines. By using a Bax deficient cancer cell line, they identified increased mitochondrial outer membrane permeability and depolarization as a mechanism of shear stress–induced TRAIL-mediated apoptosis. The research team also developed computational models to simulate TRAIL-mediated apoptosis and to identify the roles of crucial proteins within the mitochondrial-apoptotic signaling pathway.

Exploitation of shear stress–induced TRAIL sensitization appears promising in a wide array of cancer types; however, this work presents a caveat. The authors demonstrated that Yoda1 induced TRAIL sensitization in noncancerous human endothelial cells to the same degree or greater than several cancer lines. It is unclear, then, whether the cancer specificity of TRAIL-induced apoptosis is maintained while exploiting mechanosensitive cell receptors, supporting a need for further research. Despite this caveat, this work is promising and opens the door to targeting the shear stress sensitization of cancer cells to TRAIL-mediated apoptosis in clinical applications.

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