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 C. Prip-Buus (2, 1) , Daniel Ricquier (1, 2) , Claire Pecqueur (5) , Sandra Guilmeau (1, 2) , Marie-Clotilde Alves-Guerra (1, 2)

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 USPC - Université Sorbonne Paris Cité
3 UPD7 - Université Paris Diderot - Paris 7
4 Hôpital Avicenne [AP-HP]
5 CRCINA-ÉQUIPE 9 - Apoptosis and Tumor Progression

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.

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

Domaines: Sciences du Vivant [q-bio]

Esther Aguilar, Pauline Esteves, Tiphaine Sancerni, Véronique Lenoir, Thomas Aparicio, et al.. UCP2 Deficiency Increases Colon Tumorigenesis by Promoting Lipid Synthesis and Depleting NADPH for Antioxidant Defenses. Cell Reports, 2019, 28 (9), pp.2306-2316.e5. ⟨10.1016/j.celrep.2019.07.097⟩. ⟨inserm-02345411⟩