{"title":"乔尔金内酯 B 通过靶向泛凋亡分子开关 Caspase-8 抑制胃癌生长","authors":"Chenhui Ma, Lei Gao, Kewei Song, Baohong Gu, Bofang Wang, Weigao Pu, Hao Chen","doi":"10.7150/jca.101218","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> To elucidate the mechanisms by which Jolkinolide B (JB), derived from Euphorbia fischeriana, suppresses gastric cancer (GC) development, given its known potent antitumor effects and the lack of detailed understanding of its impact and molecular processes in GC. <b>Methods:</b> The study utilized both cellular and animal models to investigate the effects of JB on GC. The GC cell lines AGS and MKN45 were used to assess JB's impact on cell growth, proliferation, migration, and invasion. Molecular techniques, including molecular docking and dynamics simulations, were employed to explore the binding interactions between JB and caspase-8. The inhibitor Z-IETD-FMK was used to examine the role of caspase-8 in JB-mediated PANoptosis. Xenograft tumor transplantation experiments were conducted to evaluate JB's effect on tumor growth and biotoxicity <i>in vivo</i>. <b>Results:</b> JB markedly inhibited the growth, proliferation, migration, and invasion of the AGS and MKN45 GC cell lines. It induced PANoptosis in GC cells by activating caspase-8, leading to increased expression of cleaved caspase-3/7 (apoptosis), GSDMD-N (pyroptosis), and p-RIPK1 and p-MLKL (necroptosis). Molecular docking and dynamics simulations revealed that JB binds effectively to caspase-8 with a binding free energy (ΔTotal) of -34.41 kcal/mol, suggesting specific binding-induced caspase-8 activation. The inhibition of caspase-8 by Z-IETD-FMK prevented JB-mediated PANoptosis. Additionally, JB significantly reduced tumor growth in xenograft models without causing biotoxicity. <b>Conclusion:</b> JB is a promising bioactive agent that inhibits gastric cancer growth through the activation of the PANoptosis pathway. This study highlights JB's potential as an effective therapeutic option for GC, underlining the importance of its binding interaction with caspase-8 and subsequent activation of apoptotic, pyroptotic, and necroptotic pathways.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"15 18","pages":"6038-6051"},"PeriodicalIF":3.3000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493019/pdf/","citationCount":"0","resultStr":"{\"title\":\"Jolkinolide B Inhibits Gastric Cancer Growth by Targeting the PANoptosis Molecular Switch Caspase-8.\",\"authors\":\"Chenhui Ma, Lei Gao, Kewei Song, Baohong Gu, Bofang Wang, Weigao Pu, Hao Chen\",\"doi\":\"10.7150/jca.101218\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> To elucidate the mechanisms by which Jolkinolide B (JB), derived from Euphorbia fischeriana, suppresses gastric cancer (GC) development, given its known potent antitumor effects and the lack of detailed understanding of its impact and molecular processes in GC. <b>Methods:</b> The study utilized both cellular and animal models to investigate the effects of JB on GC. The GC cell lines AGS and MKN45 were used to assess JB's impact on cell growth, proliferation, migration, and invasion. Molecular techniques, including molecular docking and dynamics simulations, were employed to explore the binding interactions between JB and caspase-8. The inhibitor Z-IETD-FMK was used to examine the role of caspase-8 in JB-mediated PANoptosis. Xenograft tumor transplantation experiments were conducted to evaluate JB's effect on tumor growth and biotoxicity <i>in vivo</i>. <b>Results:</b> JB markedly inhibited the growth, proliferation, migration, and invasion of the AGS and MKN45 GC cell lines. It induced PANoptosis in GC cells by activating caspase-8, leading to increased expression of cleaved caspase-3/7 (apoptosis), GSDMD-N (pyroptosis), and p-RIPK1 and p-MLKL (necroptosis). Molecular docking and dynamics simulations revealed that JB binds effectively to caspase-8 with a binding free energy (ΔTotal) of -34.41 kcal/mol, suggesting specific binding-induced caspase-8 activation. The inhibition of caspase-8 by Z-IETD-FMK prevented JB-mediated PANoptosis. Additionally, JB significantly reduced tumor growth in xenograft models without causing biotoxicity. <b>Conclusion:</b> JB is a promising bioactive agent that inhibits gastric cancer growth through the activation of the PANoptosis pathway. This study highlights JB's potential as an effective therapeutic option for GC, underlining the importance of its binding interaction with caspase-8 and subsequent activation of apoptotic, pyroptotic, and necroptotic pathways.</p>\",\"PeriodicalId\":15183,\"journal\":{\"name\":\"Journal of Cancer\",\"volume\":\"15 18\",\"pages\":\"6038-6051\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493019/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/jca.101218\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/jca.101218","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
Jolkinolide B Inhibits Gastric Cancer Growth by Targeting the PANoptosis Molecular Switch Caspase-8.
Background: To elucidate the mechanisms by which Jolkinolide B (JB), derived from Euphorbia fischeriana, suppresses gastric cancer (GC) development, given its known potent antitumor effects and the lack of detailed understanding of its impact and molecular processes in GC. Methods: The study utilized both cellular and animal models to investigate the effects of JB on GC. The GC cell lines AGS and MKN45 were used to assess JB's impact on cell growth, proliferation, migration, and invasion. Molecular techniques, including molecular docking and dynamics simulations, were employed to explore the binding interactions between JB and caspase-8. The inhibitor Z-IETD-FMK was used to examine the role of caspase-8 in JB-mediated PANoptosis. Xenograft tumor transplantation experiments were conducted to evaluate JB's effect on tumor growth and biotoxicity in vivo. Results: JB markedly inhibited the growth, proliferation, migration, and invasion of the AGS and MKN45 GC cell lines. It induced PANoptosis in GC cells by activating caspase-8, leading to increased expression of cleaved caspase-3/7 (apoptosis), GSDMD-N (pyroptosis), and p-RIPK1 and p-MLKL (necroptosis). Molecular docking and dynamics simulations revealed that JB binds effectively to caspase-8 with a binding free energy (ΔTotal) of -34.41 kcal/mol, suggesting specific binding-induced caspase-8 activation. The inhibition of caspase-8 by Z-IETD-FMK prevented JB-mediated PANoptosis. Additionally, JB significantly reduced tumor growth in xenograft models without causing biotoxicity. Conclusion: JB is a promising bioactive agent that inhibits gastric cancer growth through the activation of the PANoptosis pathway. This study highlights JB's potential as an effective therapeutic option for GC, underlining the importance of its binding interaction with caspase-8 and subsequent activation of apoptotic, pyroptotic, and necroptotic pathways.
期刊介绍:
Journal of Cancer is an open access, peer-reviewed journal with broad scope covering all areas of cancer research, especially novel concepts, new methods, new regimens, new therapeutic agents, and alternative approaches for early detection and intervention of cancer. The Journal is supported by an international editorial board consisting of a distinguished team of cancer researchers. Journal of Cancer aims at rapid publication of high quality results in cancer research while maintaining rigorous peer-review process.