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A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma.
Jiang, Xifei; Deng, Wenjia; Tao, Siyao; Tang, Zheng; Chen, Yuehong; Tian, Mengxin; Wang, Ting; Tao, Chenyang; Li, Yize; Fang, Yuan; Pu, Congying; Gao, Jun; Wang, Xiaomin; Qu, Weifeng; Gai, Xiameng; Ding, Zhenbin; Fu, Yixian; Zheng, Ying; Cao, Siyuwei; Zhou, Jian; Huang, Min; Liu, Weiren; Xu, Jun; Fan, Jia; Shi, Yinghong.
Afiliación
  • Jiang X; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Deng W; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
  • Tao S; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Tang Z; University of Chinese Academy of Sciences, Beijing, China.
  • Chen Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Tian M; University of Chinese Academy of Sciences, Beijing, China.
  • Wang T; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Tao C; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
  • Li Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Fang Y; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Pu C; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Gao J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Wang X; University of Chinese Academy of Sciences, Beijing, China.
  • Qu W; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Gai X; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
  • Ding Z; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Fu Y; University of Chinese Academy of Sciences, Beijing, China.
  • Zheng Y; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Cao S; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
  • Zhou J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Huang M; University of Chinese Academy of Sciences, Beijing, China.
  • Liu W; Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University & Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Shanghai, China.
  • Xu J; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
  • Fan J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • Shi Y; University of Chinese Academy of Sciences, Beijing, China.
Cell Discov ; 9(1): 7, 2023 Jan 17.
Article en En | MEDLINE | ID: mdl-36650126
Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Discov Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Discov Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido