Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer

Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non-muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset...

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Bibliographic Details
Published in:Science translational medicine 2021-01, Vol.13 (575)
Main Authors: Oresta, Bianca, Pozzi, Chiara, Braga, Daniele, Hurle, Rodolfo, Lazzeri, Massimo, Colombo, Piergiuseppe, Frego, Nicola, Erreni, Marco, Faccani, Cristina, Elefante, Grazia, Barcella, Matteo, Guazzoni, Giorgio, Rescigno, Maria
Format: Article
Language:English
Subjects:
Apoptosis
Bladder cancer
Cancer
Cell death
Chemotherapy
Cytotoxicity
Dendritic cells
Electron transport chain
IL-1β
Immunogenicity
Inflammasomes
Invasiveness
Metabolism
Mitochondrial DNA
Mitomycin C
Oxidative phosphorylation
Permeability
Phosphorylation
Tumor cells
Tumors
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Summary:Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non-muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1β (interleukin-1β) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aba6110