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. 2019 Jun 12;14(6):e0218126.
doi: 10.1371/journal.pone.0218126. eCollection 2019.

Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation

Aviva Rabin-Court  1   2 , Marcos R Rodrigues  1 , Xian-Man Zhang  1 , Rachel J Perry  1   2
Affiliations

Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation

Aviva Rabin-Court et al. PLoS One. .

Abstract

Obesity is associated with increased incidence and worse prognosis of more than one dozen tumor types; however, the molecular mechanisms for this association remain under debate. We hypothesized that insulin, which is elevated in obesity-driven insulin resistance, would increase tumor glucose oxidation in obesity-associated tumors. To test this hypothesis, we applied and validated a stable isotope method to measure the ratio of pyruvate dehydrogenase flux to citrate synthase flux (VPDH/VCS, i.e. the percent of total mitochondrial oxidation fueled by glucose) in tumor cells. Using this method, we found that three tumor cell lines associated with obesity (colon cancer [MC38], breast cancer [4T1], and prostate cancer [TRAMP-C3] cells) increase VPDH/VCS in response to physiologic concentrations of insulin. In contrast, three tumor cell lines that are not associated with obesity (melanoma [YUMM1.7], B cell lymphoma [BCL1 clone 5B1b], and small cell lung cancer [NCI-H69] cells) exhibited no oxidative response to insulin. The observed increase in glucose oxidation in response to insulin correlated with a dose-dependent increase in cell division in obesity-associated tumor cell lines when grown in insulin, whereas no alteration in cell division was seen in tumor types not associated with obesity. These data reveal that a shift in substrate preference in the setting of physiologic insulin may comprise a metabolic signature of obesity-associated tumors that differs from that of those not associated with obesity.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Insulin receptor expression and insulin-stimulated insulin receptor phosphorylation do not correlate with tumor cell lines’ association with obesity.
(A) Insulin receptor expression. The data are the mean ± S.E.M. of six replicates from each cell line, including cells with and without insulin. **P<0.01 by ANOVA with Bonferroni’s multiple comparisons test. (B) Insulin receptor Tyr1162 phosphorylation. The data are presented as fold change from baseline, representing cells from the same cell line without insulin. *P<0.05, **P<0.01, ***P<0.001 by the 2-tailed unpaired Student’s t-test. Data are the mean ± S.E.M. of n = 3 per condition.
Fig 2
Fig 2. Tumor types associated with obesity, but not those not associated with obesity, increase mitochondrial glucose oxidation in the presence of insulin.
(A) Glucose uptake. (B) VPDH/VCS. (C) Absolute rates of glucose oxidation. In all panels, data are the mean ± S.E.M. of n = 5–9 replicates per condition, with cells from the same line ± insulin compared using the 2-tailed unpaired Student’s t-test.
Fig 3
Fig 3. The stable isotope method applied in this study is sensitive to detect the expected differences in VPDH/VCS with physiologic alterations in these fluxes, and is not affected by physiologically relevant glutamine or ketone concentrations.
(A) Glutamine in the physiologic range (0–10 mM) does not significantly affect the measured VPDH/VCS in MC38 or YUMM1.7 cells. n = 4 replicates per condition, with comparisons by ANOVA with Bonferroni’s multiple comparisons test. (B) β-OHB in the physiologic range (0–2 mM) does not significantly alter the measured VPDH/VCS in MC38 or YUMM1.7 cells. Conditions were compared by the 2-tailed unpaired Student’s t-test. In panels (B)-(D), n = 6–9 replicates per condition. (C) Vβ-OHB-ox/VCS is minimal in MC38 and YUMM1.7 cells. (D) VPDH/VCS is increased with inhibition of fatty acid oxidation (etomoxir) or stimulation of PDH (dichloroacetate), and decreased with inhibition of PDH (6,8-bis(benzylthio)octanoic acid). Groups were compared by ANOVA with Bonferroni’s multiple comparisons test. In all panels, data are the mean ± S.E.M.
Fig 4
Fig 4. PDH activity promotes tumor growth in both obesity-associated and obesity-independent tumor cell lines.
(A) Cell division in tumor cell lines incubated with or without insulin, with or without a PDH inhibitor. (B) Cell division in tumor cell lines incubated with or without the PDH activator dichloroacetate. In both panels, n = 6 replicates per condition, normalized to controls from the same cell line. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 by ANOVA with Bonferroni’s multiple comparisons test (panel (A)) or by the 2-tailed unpaired Student’s t-test (panel (B)). Data are the mean± S.E.M.
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