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The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity.
Santavanond, Jascinta P; Chiu, Yu-Hsin; Tixeira, Rochelle; Liu, Zonghan; Yap, Jeremy K Y; Chen, Kaiwen W; Li, Chen-Lu; Lu, Yi-Ru; Roncero-Carol, Joan; Hoijman, Esteban; Rutter, Stephanie F; Shi, Bo; Ryan, Gemma F; Hodge, Amy L; Caruso, Sarah; Baxter, Amy A; Ozkocak, Dilara C; Johnson, Chad; Day, Zoe I; Mayfosh, Alyce J; Hulett, Mark D; Phan, Thanh K; Atkin-Smith, Georgia K; Poon, Ivan K H.
Afiliación
  • Santavanond JP; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
  • Chiu YH; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.
  • Tixeira R; Departments of Medical Science, Life Science, and Medicine, National Tsing Hua University, Hsinchu, Taiwan. yhchiu@life.nthu.edu.tw.
  • Liu Z; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan. yhchiu@life.nthu.edu.tw.
  • Yap JKY; Unit for Cell Clearance in Health and Disease, VIB Center for Inflammation Research, Ghent, Belgium.
  • Chen KW; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • Li CL; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Lu YR; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
  • Roncero-Carol J; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Hoijman E; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
  • Rutter SF; Immunology Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • Shi B; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
  • Ryan GF; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
  • Hodge AL; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
  • Caruso S; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.
  • Baxter AA; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • Ozkocak DC; Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL), Barcelona, Spain.
  • Johnson C; Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • Day ZI; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
  • Mayfosh AJ; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.
  • Hulett MD; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
  • Phan TK; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.
  • Atkin-Smith GK; Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
  • Poon IKH; Research Centre of Extracellular Vesicles, La Trobe University, Melbourne, Victoria, Australia.
Cell Death Dis ; 15(2): 123, 2024 02 09.
Article en En | MEDLINE | ID: mdl-38336804
ABSTRACT
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Apoptosis / Conexinas / Fluorenos Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: Australia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Apoptosis / Conexinas / Fluorenos Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: Australia