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Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer

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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.

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Data will be made available on reasonable request.

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Acknowledgements

We thank Dr Virginie André, Julien Sobilo, and Isabelle Domingo for technical assistance. Inserm UMR 1069 is leader of Cancéropole Grand-Ouest 3MC network (Marine Molecules, Metabolism and Cancer), member of Région Centre—Val de Loire thematic research consortium RTR MOTIVHEALTH (Molecular and Technological Innovation for Health) and member of CNRS research group APPICOM (Integrative Approach for a multiscale functional analysis of membrane proteins). We acknowledge Inserm, Université de Tours and Région Centre-Val de Loire for their financial supports.

Funding

This project was partly supported by grants on behalf of the following french department committees of Ligue Contre le Cancer Grand-Ouest: 16 (Charente), 37 (Indre-et-Loire), 49 (Maine-et-Loire), 72 (Sarthe) and 85 (Vendée). Maxime Guéguinou is a recipient of a 3-years postdoctoral grant from Région Centre—Val de Loire (Opticoregumine project). Sajida Ibrahim was partly funded by ARFMAD (Association Recherche et Formation dans les Maladies de l’Appareil Digestif). Alison Robert is a recipient of a 3-years doctoral grant from Inserm/ Région Centre – Val de Loire. David Crottès is a recipient of SMART LOIRE VALLEY fellowship from LE STUDIUM Loire Valley Institute for Advanced Studies. COLOMIN cohort was supported in part by a grant from the association “Sport et Collection” and “Ligue Contre le Cancer, Comités départementaux de la Vienne, Charente et Charente-Maritime” (David Tougeron).

Author information

Author notes

  1. William Raoul and Thierry Lecomte (senior authors) have contributed equally to this work.

Authors and Affiliations

  1. EA 7501 GICC, Université de Tours, Tours, France

    Maxime Guéguinou, Sajida Ibrahim, David Ternant, Romain Chautard, William Raoul & Thierry Lecomte

  2. CNRS ERL 7001 LNOx, Tours, France

    Jérôme Bourgeais & Olivier Hérault

  3. N2C, Nutrition Growth and Cancer, Faculté de Médecine, Université de Tours, Inserm, UMR 1069, Tours, France

    Maxime Guéguinou, Alison Robert, David Crottès, Roseline Guibon, Jean-François Dumas, Philippe G. Frank, Gaëlle Fromont-Hankard, Christophe Vandier, William Raoul & Thierry Lecomte

  4. Department of Cellular and Molecular Physiology, College of Medicine, The Pennsylvania State University, 500 University Dr, Hershey, PA, 17033, USA

    Trayambak Pathak, Xuexin Zhang & Mohamed Trebak

  5. TOXALIM (Research Centre in Food Toxicology)-Team E9-PPCA, Université de Toulouse, UMR 1331 INRAE, ENVT, INP-Purpan, UPS, Toulouse, France

    Jacques Dupuy & Françoise Guéraud

  6. EA4245 Transplant Immunology and Inflammation, Université de Tours, 10 Boulevard Tonnellé, 37032, Tours, France

    David Ternant & Mehdi Ouaissi

  7. IRMAR Mathematics Research Institute of Rennes, UMR-CNRS 6625, Rennes, France

    Valérie Monbet

  8. Institute for Genetics, University of Cologne, Cologne, Germany

    Hector Flores-Romero & Ana J. García-Sáez

  9. Cologne Excellence Cluster On Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Hector Flores-Romero & Ana J. García-Sáez

  10. Interfaculty Institute of Biochemistry, Eberhard-Karls-Universität Tübingen, Tübingen, Germany

    Hector Flores-Romero & Ana J. García-Sáez

  11. UMR 1253, iBrain, Université de Tours, Inserm, 37000, Tours, France

    Antoine Lefèvre & Patrick Emond

  12. CNRS UPS44, CIPA, PHENOMIN-TAAM, Orléans, France

    Stéphanie Lerondel & Alain Le Pape

  13. Laboratory of Cellular and Molecular Physiology, UR UPJV 4667, University of Picardie Jules Verne, Amiens, France

    Alban Girault

  14. IRDL Institut de Recherche Dupuy de Lôme, UMR-CNRS, 06027, Vannes, France

    Olivier Sire

  15. Hepato-Gastroenterology Department, Poitiers University Hospital and Faculty of Medicine of Poitiers, 86000, Poitiers, France

    David Tougeron

  16. Department of Hepato-Gastroenterology and Digestive Oncology, CHRU de Tours, Tours, France

    Thierry Lecomte

Authors
  1. Maxime Guéguinou
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  2. Sajida Ibrahim
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  3. Jérôme Bourgeais
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  4. Alison Robert
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  6. Xuexin Zhang
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  7. David Crottès
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  8. Jacques Dupuy
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  9. David Ternant
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  18. Alban Girault
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  19. Romain Chautard
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  21. Ana J. García-Sáez
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  23. Patrick Emond
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  26. Gaëlle Fromont-Hankard
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  27. Christophe Vandier
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  28. David Tougeron
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  29. Mohamed Trebak
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  30. William Raoul
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  31. Thierry Lecomte
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Contributions

Study concept and design: MG, WR, and TL. Acquisition of data: MG, SI, JB, AR, TP, XZ, JD, DT, RG, HFR, AL, SL, RC, MO, OS, OH, GFH, DTo, and TL. Analysis and interpretation of data: MG, SI, JB, AR, TP, XZ, DC, JD, DT, VM, HFR, AL, SL, ALP, JFD, PGF, AG, RC, FG, AJGS, PE, OS, OH, GFH, CV, DTo, MT, WR, and TL. Drafting of the manuscript: MG, SI, JB, PE, OS, CV, DTo, MT, WR, and TL. Critical revision of the manuscript for important intellectual content: All. Statistical analysis: MG, SI, JB, VM, PE, DTo, WR, and TL. Obtained funding: MG, AG, DTo, WR, and TL. Study supervision: MG, WR, and TL.

Corresponding authors

Correspondence to Maxime Guéguinou or Thierry Lecomte.

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No competing interests were disclosed by authors.

Ethics approval and consent to participate

COLOMIN study was designed in accordance with legal requirements and the Declaration of Helsinki, and was approved by the ethics committee of CHU Poitiers and CHRU Tours, France (Comité de protection des personnes Ouest III, no. DC-2008-565 and no. 2018-039).

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Guéguinou, M., Ibrahim, S., Bourgeais, J. et al. Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer. Cell. Mol. Life Sci. 79, 284 (2022). https://doi.org/10.1007/s00018-022-04311-4

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