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

Autor:	Santavanond JP; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Chiu YH; Departments of Medical Science, Life Science, and Medicine, National Tsing Hua University, Hsinchu, Taiwan. yhchiu@life.nthu.edu.tw.; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan. yhchiu@life.nthu.edu.tw., Tixeira R; Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Liu Z; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore., Yap JKY; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore., Chen KW; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore., Li CL; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan., Lu YR; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan., Roncero-Carol J; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain., Hoijman E; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain., Rutter SF; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Shi B; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Ryan GF; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Hodge AL; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Caruso S; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Baxter AA; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Ozkocak DC; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Johnson C; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia., Day ZI; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia., Mayfosh AJ; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia., Hulett MD; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia., Phan TK; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.; The Walter and Eliza Hall Institute of Medial Research, Parkville, Vic, Australia., Atkin-Smith GK; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.; The Walter and Eliza Hall Institute of Medial Research, Parkville, Vic, Australia.; University of Melbourne, Melbourne, VIC, Australia., Poon IKH; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia. i.poon@latrobe.edu.au.; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia. i.poon@latrobe.edu.au.
Jazyk:	angličtina
Zdroj:	Cell death & disease [Cell Death Dis] 2024 Feb 09; Vol. 15 (2), pp. 123. Date of Electronic Publication: 2024 Feb 09.
DOI:	10.1038/s41419-024-06513-z
Abstrakt:	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 of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors. (© 2024. The Author(s).)
Databáze:	MEDLINE
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