| Summary: | Summary: 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. : Aguilar et al. show that the inhibition of mitochondrial transporter UCP2 increases susceptibility to colon and intestinal tumorigenesis and correlates with poor prognosis. The underlying mechanisms involve deregulation of redox homeostasis through metabolic rewiring. Thus, UCP2 plays a key role in CRC, and its loss is potentially associated with worse outcomes. Keywords: uncoupling protein 2, mitochondrial carrier, tumor metabolic reprogramming, oxidative stress, colorectal cancer, lipid synthesis, mitochondria, tumor metabolism
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