Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice

SIMPLE SUMMARY: If improvements of diagnostic techniques and methodologies allow to increasingly detect cancers at the premetastatic stage, metastases still account for about 90% of cancer patient deaths in the clinics. Indeed, there is currently no specific treatment capable of blocking or even del...

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Autores principales: Capeloa, Tania, Van de Velde, Justine A., d’Hose, Donatienne, Lipari, Sara G., Derouane, Françoise, Hamelin, Loïc, Bedin, Marie, Vazeille, Thibaut, Duhoux, François P., Murphy, Michael P., Porporato, Paolo E., Gallez, Bernard, Sonveaux, Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9562676/
https://www.ncbi.nlm.nih.gov/pubmed/36230841
http://dx.doi.org/10.3390/cancers14194918
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author Capeloa, Tania
Van de Velde, Justine A.
d’Hose, Donatienne
Lipari, Sara G.
Derouane, Françoise
Hamelin, Loïc
Bedin, Marie
Vazeille, Thibaut
Duhoux, François P.
Murphy, Michael P.
Porporato, Paolo E.
Gallez, Bernard
Sonveaux, Pierre
author_facet Capeloa, Tania
Van de Velde, Justine A.
d’Hose, Donatienne
Lipari, Sara G.
Derouane, Françoise
Hamelin, Loïc
Bedin, Marie
Vazeille, Thibaut
Duhoux, François P.
Murphy, Michael P.
Porporato, Paolo E.
Gallez, Bernard
Sonveaux, Pierre
author_sort Capeloa, Tania
collection PubMed
description SIMPLE SUMMARY: If improvements of diagnostic techniques and methodologies allow to increasingly detect cancers at the premetastatic stage, metastases still account for about 90% of cancer patient deaths in the clinics. Indeed, there is currently no specific treatment capable of blocking or even delaying the metastatic process. In this context, we previously showed that mitochondria are metabolic sensors initiating the metastatic process. Here, focusing on pancreatic cancer, with which about one-third of patients are diagnosed before the onset of metastases, we report that MitoQ, a mitochondria-targeted antioxidant, interrupts prometastatic redox signaling from mitochondria to the cell body. At doses compatible with the treatment of humans, we found that MitoQ represses pancreatic cancer cell migration, invasion and clonogenicity. It reduced the metastatic homing of human pancreatic cancer cells in mice by about 50%. If applied to patients, metastasis prevention with MitoQ could increase the chances of curing cancer with conventional treatments. ABSTRACT: At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100–500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by ~50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer.
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spelling pubmed-95626762022-10-15 Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice Capeloa, Tania Van de Velde, Justine A. d’Hose, Donatienne Lipari, Sara G. Derouane, Françoise Hamelin, Loïc Bedin, Marie Vazeille, Thibaut Duhoux, François P. Murphy, Michael P. Porporato, Paolo E. Gallez, Bernard Sonveaux, Pierre Cancers (Basel) Article SIMPLE SUMMARY: If improvements of diagnostic techniques and methodologies allow to increasingly detect cancers at the premetastatic stage, metastases still account for about 90% of cancer patient deaths in the clinics. Indeed, there is currently no specific treatment capable of blocking or even delaying the metastatic process. In this context, we previously showed that mitochondria are metabolic sensors initiating the metastatic process. Here, focusing on pancreatic cancer, with which about one-third of patients are diagnosed before the onset of metastases, we report that MitoQ, a mitochondria-targeted antioxidant, interrupts prometastatic redox signaling from mitochondria to the cell body. At doses compatible with the treatment of humans, we found that MitoQ represses pancreatic cancer cell migration, invasion and clonogenicity. It reduced the metastatic homing of human pancreatic cancer cells in mice by about 50%. If applied to patients, metastasis prevention with MitoQ could increase the chances of curing cancer with conventional treatments. ABSTRACT: At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100–500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by ~50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer. MDPI 2022-10-07 /pmc/articles/PMC9562676/ /pubmed/36230841 http://dx.doi.org/10.3390/cancers14194918 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Capeloa, Tania
Van de Velde, Justine A.
d’Hose, Donatienne
Lipari, Sara G.
Derouane, Françoise
Hamelin, Loïc
Bedin, Marie
Vazeille, Thibaut
Duhoux, François P.
Murphy, Michael P.
Porporato, Paolo E.
Gallez, Bernard
Sonveaux, Pierre
Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title_full Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title_fullStr Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title_full_unstemmed Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title_short Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice
title_sort inhibition of mitochondrial redox signaling with mitoq prevents metastasis of human pancreatic cancer in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9562676/
https://www.ncbi.nlm.nih.gov/pubmed/36230841
http://dx.doi.org/10.3390/cancers14194918
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