Volume 24, Issue 1, Pages (July 2018)

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Volume 24, Issue 1, Pages 47-55 (July 2018) Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer  Yongliang Wang, Ali R. Nasiri, William E. Damsky, Curtis J. Perry, Xian-Man Zhang, Aviva Rabin-Court, Michael N. Pollak, Gerald I. Shulman, Rachel J. Perry  Cell Reports  Volume 24, Issue 1, Pages 47-55 (July 2018) DOI: 10.1016/j.celrep.2018.06.008 Copyright © 2018 The Authors Terms and Conditions

Cell Reports 2018 24, 47-55DOI: (10.1016/j.celrep.2018.06.008) Copyright © 2018 The Authors Terms and Conditions

Figure 1 Liver-Targeted Mitochondrial Uncoupling with a Controlled-Release Mitochondrial Protonophore Reverses Fasting Hyperglycemia and Hyperinsulinemia in HFD MC38 Tumor-Bearing Mice (A) Plasma DNP concentration in tumor-bearing mice given ad lib access to food containing controlled-release mitochondrial protonophore. (B) Plasma, liver, and tumor DNP concentrations measured in a separate group of ad lib-fed mice at 10 a.m. (C and D) Fasting plasma glucose (C) and insulin concentrations (D). (E) Endogenous glucose production. (F) Plasma non-esterified fatty acid concentrations. (G and H) Liver (G) and quadriceps (H) triglyceride content. In (A) and (B), n = 4. In (C)–(H), n = 7 HFD mice and 8 in all other groups. Data are the mean ± SEM, with comparisons by ANOVA with Bonferroni’s multiple comparisons test. See also Figure S1. Cell Reports 2018 24, 47-55DOI: (10.1016/j.celrep.2018.06.008) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Controlled-Release Mitochondrial Protonophore Slows MC38 Tumor Growth and Limits Tumor Glucose Uptake and Oxidation due to Reversal of Hyperinsulinemia (A) Tumor size. (B) In vitro proliferation of cells incubated in media containing DNP. Data are the mean ± SEM of 6 replicate wells for each condition, each counted in duplicate. The two conditions were compared by the two-tailed unpaired Student’s t test. (C and D) Tumor glucose uptake (C) and oxidation (VPDH/VCS) (D). (E and F) Plasma acetate concentrations (E) and whole-body acetate turnover (F). (G) Ratio of tumor to plasma acetate enrichment in mice infused with [1-13C] acetate. (H) Ratio of tumor TCA cycle intermediate enrichment to plasma acetate enrichment in mice infused with [1-13C] acetate. In (A) and (C)–(H), n = 7 HFD mice and 8 in all other groups. In all panels, data are the mean ± SEM with comparisons by ANOVA with Bonferroni’s multiple comparisons test unless otherwise stated. Cell Reports 2018 24, 47-55DOI: (10.1016/j.celrep.2018.06.008) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Controlled-Release Mitochondrial Protonophore Slows Tumor Growth in High-Fat-Fed ApcMin+/− Mice, a Murine Model of Familial Adenomatous Polyposis, by Reversing Hyperinsulinemia (A and B) Fasting plasma glucose (A) and insulin concentrations (B). (C) Representative images of small intestine stained for β-catenin. (D and E) Quantification of total polyp number (D) and area (E). (F and G) Tumor glucose uptake (F) and oxidation (VPDH/VCS) (G). In (A)–(E), n = 5 per group. In (F) and (G), n = 4–5 per group. In all panels, data are the mean ± SEM and groups were compared by ANOVA with Bonferroni’s multiple comparisons test. See also Figure S2. Cell Reports 2018 24, 47-55DOI: (10.1016/j.celrep.2018.06.008) Copyright © 2018 The Authors Terms and Conditions

Figure 4 Metformin Slows Tumor Growth in HFD Mice by Reducing Tumor Glucose Uptake and Oxidation Secondary to Hyperinsulinemia (A) Plasma, liver, and tumor metformin concentrations. (B and C) Fasting plasma glucose (B) and insulin concentrations (C). (D) Endogenous glucose turnover. (E) Tumor size. (F) In vitro proliferation of MC38 cells incubated in media containing metformin. (G and H) Tumor glucose uptake (G) and oxidation (VPDH/VCS) (H). In (A), n = 6. In (B)–(H), data are the mean ± SEM of n = 8 per group, with comparisons by ANOVA with Bonferroni’s multiple comparisons test. See also Figure S3. Cell Reports 2018 24, 47-55DOI: (10.1016/j.celrep.2018.06.008) Copyright © 2018 The Authors Terms and Conditions