Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation
- PMID: 31188872
- PMCID: PMC6561592
- DOI: 10.1371/journal.pone.0218126
Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation
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.
Conflict of interest statement
The authors have declared that no competing interests exist.
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References
-
- Limburg PJ, Stolzenberg-Solomon RZ, Vierkant RA, Roberts K, Sellers TA, Taylor PR, et al. Insulin, glucose, insulin resistance, and incident colorectal cancer in male smokers. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. 2006;4(12):1514–21. 10.1016/j.cgh.2006.09.014 - DOI - PMC - PubMed
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