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Targeting the MCP-GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma.
Li, Ge; Liao, Chengyu; Chen, Jiangzhi; Wang, Zuwei; Zhu, Shuncang; Lai, Jianlin; Li, Qiaowei; Chen, Yinhao; Wu, Dihan; Li, Jianbo; Huang, Yi; Tian, Yifeng; Chen, Yanling; Chen, Shi.
Afiliación
  • Li G; Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • Liao C; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Chen J; Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
  • Wang Z; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Zhu S; Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, China.
  • Lai J; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Li Q; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Chen Y; Department of Hepatopancreatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, China.
  • Wu D; Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China.
  • Li J; Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China.
  • Huang Y; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Tian Y; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Chen Y; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
  • Chen S; Shengli Clinical Medical College of Fujian Medical University, Fujian Medical University, Fuzhou, 350001, China.
Adv Sci (Weinh) ; 11(21): e2308208, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38593415
ABSTRACT
Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient-derived organoid models and a KPC mouse model (LSL-KrasG12D /+, LSL-Trp53R172H/+, Pdx-1-Cre). It is observed that the inhibition of macrophage-capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4, a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage-associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre-accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro-inflammatory M1-like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro-inflammatory M1-like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Proteína HMGB1 / Modelos Animales de Enfermedad / Ferroptosis / Fosfolípido Hidroperóxido Glutatión Peroxidasa Límite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Proteína HMGB1 / Modelos Animales de Enfermedad / Ferroptosis / Fosfolípido Hidroperóxido Glutatión Peroxidasa Límite: Animals / Humans Idioma: En Revista: Adv Sci (Weinh) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania