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Molecular mechanisms of ATP secretion during immunogenic cell death
Open accessAbstract
The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase- and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.
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“This said, executioner caspases can positively or negatively regulate the emission of multiple DAMPs from dying cells, including immunostimulatory [229] as well as immunosuppressive [230] factors.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [229]
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“In the context of ICD, ATP is released through a cascade of events occurring downstream of caspase activation and involving: (1) the autophagy-dependent accumulation of ATP within autolysosomes (the organelles forming by the fusion of autophagosomes or amphisomes with lysosomes), (2) the relocalization of lysosomal-associated membrane protein 1 (LAMP1) to the plasma membrane, (3) ROCK1-dependent”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [229]
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Self-citationImmunogenic Cell Death in Cancer Therapy
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Metadata
- Authors
- Martins, I., Wang, Y., Michaud, M., Ma, Y., Sukkurwala, A. Q., Shen, S., Kepp, O., Métivier, D., Galluzzi, L., Perfettini, J.-L., Zitvogel, L., & Kroemer, G.
- Affiliations
- Université Paris-Sud (FR)
- Institut Gustave Roussy (FR)
- Inserm (FR)
- Corresponding author
- Kroemer, G
- Venue
- Cell Death & Differentiation
- Published
- 2013-07-12
- Volume
- 21
- Issue
- 1
- Pages
- 79-91
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3857631
- OpenAlex
- W1991505853
- Cited by
- 563
- References
- 61
- Citations by year
- 2026: 53 · 2025: 57 · 2024: 48 · 2023: 67 · 2022: 39 · 2021: 45 · 2020: 51 · 2019: 34 · 2018: 40 · 2017: 36 · 2016: 34 · 2015: 28 · 2014: 21 · 2013: 10
- FWCI
- 13.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sidaction
- European Commission
- Agence Nationale de la Recherche
- Fondation de France
- Institut National Du Cancer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- immunogenic cell death, ATP release, lysosomal exocytosis, LAMP1, autophagy, caspase activation, Panx1 channels, ROCK1, myosin II, immunogenic chemotherapy, anthracyclines, oxaliplatin, cancer immunotherapy
- MeSH terms
- Autophagy-Related Protein 5, Adenosine Triphosphate, Animals, Antineoplastic Agents, Cell Membrane, DNA-Binding Proteins, Humans, Lysosomes, Microtubule-Associated Proteins, Nerve Tissue Proteins, RNA-Binding Proteins, Cell Death, Connexins, HMGB1 Protein, Myosin Type II, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Mice, Lysosomal-Associated Membrane Protein 1, rho-Associated Kinases
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