UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses

Esther Aguilar; Pauline Esteves; Tiphaine Sancerni; Véronique Lenoir; Thomas Aparicio; Frédéric Bouillaud; Renaud Dentin; Carina Prip-Buus; Daniel Ricquier; Claire Pecqueur; Sandra Guilmeau; Marie-Clotilde Alves-Guerra

doi:10.1016/j.celrep.2019.07.097

UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses

Esther Aguilar ^{1, 2} Pauline Esteves ^{1, 2} Tiphaine Sancerni ^{1, 2, 3} Véronique Lenoir ^{1, 2} Thomas Aparicio ⁴ Frédéric Bouillaud ^{1, 2} Renaud Dentin ^{1, 2} Carina Prip-Buus ^{2, 1} Daniel Ricquier ^{1, 2} Claire Pecqueur ⁵ Sandra Guilmeau ^{1, 2} Marie-Clotilde Alves-Guerra ^{1, 2, *}

* Corresponding author

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin

2 USPC - Université Sorbonne Paris Cité

3 UPD7 - Université Paris Diderot - Paris 7

4 Hôpital avicenne

5 CRCINA - Département ONCO - Equipe 9 - Apoptosis and tumor progression -ATP

CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers

Abstract : Colorectal cancer (CRC) is associated with metabolic and redox perturbation. The mitochondrial transporter uncoupling protein 2 (UCP2) controls cell proliferation in vitro through the modulation of cellular metabolism, but the underlying mechanism in tumors in vivo remains unexplored. Using murine intestinal cancer models and CRC patient samples, we find higher UCP2 protein levels in tumors compared to their non-tumoral counterparts. We reveal the tumor-suppressive role of UCP2 as its deletion enhances colon and small intestinal tumorigenesis in AOM/DSS-treated and ApcMin/+ mice, respectively, and correlates with poor survival in the latter model. Mechanistically, UCP2 loss increases levels of oxidized glutathione and proteins in tumors. UCP2 deficiency alters glycolytic pathways while promoting phospholipid synthesis, thereby limiting the availability of NADPH for buffering oxidative stress. We show that UCP2 loss renders colon cells more prone to malignant transformation through metabolic reprogramming and perturbation of redox homeostasis and could favor worse outcomes in CRC.

Keywords : colorectal cancer lipid synthesis mitochondria mitochondrial carrier oxidative stress tumor metabolic reprogramming tumor metabolism uncoupling protein 2

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Journal articles

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Life Sciences [q-bio]

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https://www.hal.inserm.fr/inserm-02345411
Contributor : Carina Prip-Buus <>
Submitted on : Tuesday, November 5, 2019 - 1:23:41 PM
Last modification on : Wednesday, November 6, 2019 - 1:50:41 AM

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UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses

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UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses

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