TY - JOUR
T1 - Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer
AU - Guéguinou, Maxime
AU - Ibrahim, Sajida
AU - Bourgeais, Jérôme
AU - Robert, Alison
AU - Pathak, Trayambak
AU - Zhang, Xuexin
AU - Crottès, David
AU - Dupuy, Jacques
AU - Ternant, David
AU - Monbet, Valérie
AU - Guibon, Roseline
AU - Flores-Romero, Hector
AU - Lefèvre, Antoine
AU - Lerondel, Stéphanie
AU - Le Pape, Alain
AU - Dumas, Jean François
AU - Frank, Philippe G.
AU - Girault, Alban
AU - Chautard, Romain
AU - Guéraud, Françoise
AU - García-Sáez, Ana J.
AU - Ouaissi, Mehdi
AU - Emond, Patrick
AU - Sire, Olivier
AU - Hérault, Olivier
AU - Fromont-Hankard, Gaëlle
AU - Vandier, Christophe
AU - Tougeron, David
AU - Trebak, Mohamed
AU - Raoul, William
AU - Lecomte, Thierry
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85129727077
UR - https://www.scopus.com/pages/publications/85129727077#tab=citedBy
U2 - 10.1007/s00018-022-04311-4
DO - 10.1007/s00018-022-04311-4
M3 - Article
C2 - 35526196
AN - SCOPUS:85129727077
SN - 1420-682X
VL - 79
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 6
M1 - 284
ER -