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  • br UCP is a mitochondrial protein that shares sequence homol

    2020-08-18


    UCP2 is a mitochondrial protein that shares 60% sequence homology with UCP1 (mainly expressed in brown adipose tissue), which produces heat by dissipating 944808-88-2 synthesis. Several studies have demonstrated that activation of UCP2 can reverse metabolic re-programming, leading to a return toward oxidation metabolism and, more importantly, lower cell proliferation rate and tumorigenicity (Esteves et al., 2015). More recent studies employing genetic or phar-macological means have demonstrated a role of UCP2 in reducing glycolysis and the utilization of pyruvate in mitochondrial oxidation (Caron et al., 2017; Giralt and Villarroya, 2017). In accordance with this statement, we recently demonstrated that activation of UCP2 in-duced metabolic reprogramming and inhibited rectal cancer growth in mice. These anti-tumorigenesis and reprogramming effects did not occur with apoptosis or toxicity. Taken together, the increased ex-pression of UCP2 may be the underlying mechanism for the increased mitochondrial oxidation, which denies the glycolytic substrate required for the Warburg effect to sustain the proliferation and growth of rectal cancer.
    It has been widely recognized that the SIRT1/AMPK axis has been linked to tumorigenesis inhibition by regulating energy levels, thus enforcing metabolic checkpoints (Lin et al., 2015). SIRT1 serves as a master regulator of fuel metabolism and has been shown to control the expression of several mitochondrial enzymes and proteins (Li et al., 2015). Its activity is strictly regulated by an increase in levels of NAD+ as well as a decrease in NADH. Upon activation, catabolism is in-creased, and anabolism is inhibited. Bou treatment significantly de-creased NADH levels and increased the ratio of NAD+/NADH. Con-sistent with the observed reduction in NADH level, SIRT1 was activated after Bou treatment. The activation of the SIRT1 may underlie the reason for which catabolism increased and anabolism decreased in HCT-116 cells.
    PGC-1α, a widely described protein that acts as a master regulator of mitochondrial biogenesis, regulates its own gene expression in a feed-forward loop. Studies have revealed that members of the PGC-1 family of transcription coactivators can stimulate the expression of mitochondrial uncoupling proteins, such as UCP1 and UCP2 (Lin et al., 2005). In particular, UCP2 expression is intimately linked to the activity of PGC-1α in pancreatic beta-cells, and PGC-1α has been shown to stimulate UCP1 and UCP2 gene expression via binding to two proximal regions of its promoter [30]. Increasing studies have demonstrated that
    the PGC-1α/UCP axis plays a pivotal role in the regulation of energetic metabolism (Lin et al., 2005; Oberkofler et al., 2006). Bou treatment increased PGC-1α transcription activity, enriched the level of PGC-1α bound to the UCP2 promoter and activated UCP2 expression. Our study provides the molecular basis for future metabolic studies that might further clarify the alterations of cancer metabolism driven by PGC-1α/ UCP2, and these molecular modes of action may underlie the phar-maceutical effect of Bou.
    PGC-1α is a key mitochondrial biogenesis regulator and plays an undoubted role in promoting mitochondrial oxidation. SIRT1 served as a key energy sensor that physically interacted with and de-acetylated PGC-1α and regulated PGC-1α activation in vivo and in vitro (Nemoto et al., 2005). In our study, we found that Bou treatment increased SIRT1 activity and de-acetylation, and then activated PGC-1α. Mutation the enzymatic site of SIRT1 thoroughly abolished the stimulation effect of Bou, suggesting that Bou mediated PGC-1α activation in a SIRT1-dependent manner.
    5. Conclusion
    In summary, the present study shows that Bou exerts a therapeutic effect to suppress rectal cancer in the cell model and rectal cancer xe-nograft mice model by switching the Warburg effect to mitochondrial oxidation of the fuel substrates (Fig. 6/Graphic Abstract). The increased mitochondrial oxidation in cancer cells is due to an upregulation of UCP2 induced by the activation of the SIRT1/AMPK-PGC-1α axis. Our findings suggest that Bou may be a candidate drug that can be further developed or optimized for the treatment of the deadly rectal cancer.
    Conflicts of interest
    The authors declare no conflict of interest.
    Author contribution
    Acknowledgements
    References
    Derdak, Z., Fulop, P., Sabo, E., Tavares, R., Berthiaume, E.P., Resnick, M.B., Paragh, G., Wands, J.R., Baffy, G., 2006. Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappa B activation and oxidative stress.
    Esteves, P., Pecqueur, C., Alves-Guerra, M.C., 2015. UCP2 induces metabolic repro-gramming to inhibit proliferation of cancer cells. Mol. Cell Oncol. 2, 1–3.