2. Academic Validation
  3. Necrocide 1 mediates necrotic cell death and immunogenic response in human cancer cells

Necrocide 1 mediates necrotic cell death and immunogenic response in human cancer cells

  • Cell Death Dis. 2023 Apr 5;14(4):238. doi: 10.1038/s41419-023-05740-0.
Jing Zhang # 1,  Christina Trojel-Hansen # 2 3,  Jianghuang Wang # 4,  Zili Zhang 4,  Xing Wang 4,  Yuhui Qiao 4,  Huike Jiao 4,  Mickaël Michaud 5 6,  Oliver Kepp 5 6,  Marja Jäättelä 7 8,  Guido Kroemer 9 10 11,  Qing Zhong 12
Affiliations

Affiliations

  • 1 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. jingzhang@shsmu.edu.cn.
  • 2 Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France. christina.trojel@gmail.com.
  • 3 Metabolomics and Cell Biology Platform, Institut Gustave Roussy, 94805, Villejuif, France. christina.trojel@gmail.com.
  • 4 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.
  • 6 Metabolomics and Cell Biology Platform, Institut Gustave Roussy, 94805, Villejuif, France.
  • 7 Cell Death and Metabolism, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), DK-2100, Copenhagen, Denmark.
  • 8 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark.
  • 9 Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France. kroemer@orange.fr.
  • 10 Metabolomics and Cell Biology Platform, Institut Gustave Roussy, 94805, Villejuif, France. kroemer@orange.fr.
  • 11 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015, Paris, France. kroemer@orange.fr.
  • 12 Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. qingzhong@shsmu.edu.cn.
  • # Contributed equally.
PMID: 37015922 DOI: 10.1038/s41419-023-05740-0
Abstract

Many Anticancer agents induce Apoptosis, mitotic catastrophe or cellular senescence. Here, we report the functional characterization of an experimental inducer of tumor necrosis factor (TNF)-independent necrosis, necrocide-1 (NC1). NC1 (but not its stereoisomer) killed a panel of human Cancer cells (but not normal cells) at nanomolar concentrations and with a non-apoptotic, necrotic morphotype, both in vitro and in vivo. NC1-induced killing was not inhibited by Caspase blockers, anti-apoptotic BCL2 overexpression or TNFα neutralization, suggesting that NC1 elicits a bona fide necrotic pathway. However, pharmacological or genetic inhibition of Necroptosis, Pyroptosis and Ferroptosis failed to block NC1-mediated cell death. Instead, NC1 elicited Reactive Oxygen Species (ROS) production by mitochondria, and elimination of mitochondrial DNA, quenching of mitochondrial ROS, as well as blockade of mitochondrial permeability transition with cyclosporine A, interfered with NC1-induced cell death. NC1 induced hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Taken together, these data identify a previously uncharacterized signaling cascade leading to an immunogenic variant of mitochondrion-regulated necrosis, supporting the notion that eliciting regulated necrosis may constitute a valid approach for Anticancer therapy.

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