The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity

作者：Jascinta P. Santavanond, Yu‐Hsin Chiu, Rochelle Tixeira, Zonghan Liu, Jeremy Kean Yi Yap, Kaiwen Chen, Chen‐Lu Li, Yi‐Ru Lu, Joan Roncero-Carol, Esteban Hoijman, Stephanie F. Rutter, Bo Shi, Gemma F. Ryan, Amy L. Hodge, Sarah Caruso, Amy A. Baxter, Dilara C. Ozkocak, Chad Johnson, Zoe I. Day, Alyce J. Mayfosh, Mark D. Hulett, Thanh Kha Phan, Georgia K. Atkin‐Smith, Ivan K. H. Poon · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06513-z · 被引用次数：17 · 研究领域：Connexins and lens biology、Heme Oxygenase-1 and Carbon Monoxide、Cell death mechanisms and regulation

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation ...