William Raoul1,2, Thierry Lecomte3,4,5, Maxime Guéguinou6,7, Sajida Ibrahim1, Jérôme Bourgeais8, Alison Robert2, Trayambak Pathak9, Xuexin Zhang9, David Crottès2, Jacques Dupuy10, David Ternant1,11, Valérie Monbet12, Roseline Guibon2, Hector Flores-Romero13,14,15, Antoine Lefèvre16, Stéphanie Lerondel17, Alain Le Pape17, Jean-François Dumas2, Philippe G Frank2, Alban Girault18, Romain Chautard1, Françoise Guéraud10, Ana J García-Sáez13,14,15, Mehdi Ouaissi11, Patrick Emond16, Olivier Sire19, Olivier Hérault8, Gaëlle Fromont-Hankard2, Christophe Vandier2, David Tougeron20, Mohamed Trebak9. 1. EA 7501 GICC, Université de Tours, Tours, France. 2. N2C, Nutrition Growth and Cancer, Faculté de Médecine, Université de Tours, Inserm, UMR 1069, Tours, France. 3. EA 7501 GICC, Université de Tours, Tours, France. thierry.lecomte@univ-tours.fr. 4. N2C, Nutrition Growth and Cancer, Faculté de Médecine, Université de Tours, Inserm, UMR 1069, Tours, France. thierry.lecomte@univ-tours.fr. 5. Department of Hepato-Gastroenterology and Digestive Oncology, CHRU de Tours, Tours, France. thierry.lecomte@univ-tours.fr. 6. EA 7501 GICC, Université de Tours, Tours, France. maxime.gueguinou@univ-tours.fr. 7. N2C, Nutrition Growth and Cancer, Faculté de Médecine, Université de Tours, Inserm, UMR 1069, Tours, France. maxime.gueguinou@univ-tours.fr. 8. CNRS ERL 7001 LNOx, Tours, France. 9. Department of Cellular and Molecular Physiology, College of Medicine, The Pennsylvania State University, 500 University Dr, Hershey, PA, 17033, USA. 10. TOXALIM (Research Centre in Food Toxicology)-Team E9-PPCA, Université de Toulouse, UMR 1331 INRAE, ENVT, INP-Purpan, UPS, Toulouse, France. 11. EA4245 Transplant Immunology and Inflammation, Université de Tours, 10 Boulevard Tonnellé, 37032, Tours, France. 12. IRMAR Mathematics Research Institute of Rennes, UMR-CNRS 6625, Rennes, France. 13. Institute for Genetics, University of Cologne, Cologne, Germany. 14. Cologne Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. 15. Interfaculty Institute of Biochemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. 16. UMR 1253, iBrain, Université de Tours, Inserm, 37000, Tours, France. 17. CNRS UPS44, CIPA, PHENOMIN-TAAM, Orléans, France. 18. Laboratory of Cellular and Molecular Physiology, UR UPJV 4667, University of Picardie Jules Verne, Amiens, France. 19. IRDL Institut de Recherche Dupuy de Lôme, UMR-CNRS, 06027, Vannes, France. 20. Hepato-Gastroenterology Department, Poitiers University Hospital and Faculty of Medicine of Poitiers, 86000, Poitiers, France.
Abstract
BACKGROUND AND AIMS: Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX. METHODS: We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa2+) extrusion, the role of redox metabolism in this process. We evaluated their anti-tumorigenic activity in vitro and in a xenograft mouse model. We analyzed NCLX expression and associations with survival in The Cancer Genome Atlas (TCGA) dataset and in tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC. RESULTS: In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis. NCLX inhibition with pharmacological and molecular approaches reproduced the effects of curcumin. NCLX inhibitors decreased CRC tumor growth in vivo. Both transcriptomic analysis of TCGA dataset and immunohistochemical analysis of tissue microarrays demonstrated that higher NCLX expression was associated with MSI status, and for the first time, NCLX expression was significantly associated with recurrence-free survival. CONCLUSIONS: Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC.
BACKGROUND AND AIMS: Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of colorectal cancer (CRC). To overcome treatment resistance, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new inhibitor of NCLX. METHODS: We examined whether curcumin and pharmacological compounds induced the inhibition of NCLX-mediated mitochondrial calcium (mtCa2+) extrusion, the role of redox metabolism in this process. We evaluated their anti-tumorigenic activity in vitro and in a xenograft mouse model. We analyzed NCLX expression and associations with survival in The Cancer Genome Atlas (TCGA) dataset and in tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC. RESULTS: In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis. NCLX inhibition with pharmacological and molecular approaches reproduced the effects of curcumin. NCLX inhibitors decreased CRC tumor growth in vivo. Both transcriptomic analysis of TCGA dataset and immunohistochemical analysis of tissue microarrays demonstrated that higher NCLX expression was associated with MSI status, and for the first time, NCLX expression was significantly associated with recurrence-free survival. CONCLUSIONS: Our findings highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic schedule of patients with MSI CRC.
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