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

• DOI: 10.1016/j.celrep.2019.07.097
• Publication Date: 2019-08-27T14:34:21Z
• Authors: 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 Al...
• Keywords: mitochondrial carrier; Male; uncoupling protein 2; QH301-705.5; Carcinogenesis; Colon; [SDV]Life Sciences [q-bio]; [SDV.CAN]Life Sciences [q-bio]/Cancer; colorectal cancer; Article; Mice; 03 medical and health sciences; Intestine, Small; tumor metabolic reprogramming; oxidative stress; lipid synthesis; Animals; Humans; Uncoupling Protein 2; Biology (General); Aged; Aged, 80 and over; 0303 health sciences; Lipogenesis; Middle Aged; mitochondria; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; Oxidative Stress; tumor metabolism; Colorectal Neoplasms; Glycolysis; NADP

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 underlying mechanism tumors vivo remains unexplored. Using murine intestinal models CRC patient samples, we find higher UCP2 levels compared to their non-tumoral counterparts. We reveal tumor-suppressive role as its deletion enhances colon small tumorigenesis AOM/DSS-treated ApcMin/+ mice, respectively, correlates poor survival latter model. Mechanistically, loss increases oxidized glutathione proteins tumors. deficiency alters glycolytic pathways while promoting phospholipid synthesis, thereby limiting availability NADPH for buffering oxidative stress. show that renders cells more prone malignant transformation reprogramming perturbation homeostasis could favor worse outcomes CRC.