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.
Highlights
Obesity is well-known to increase the prevalence and mortality of more than one dozen tumor types
Insulin activates the insulin receptor in all tumor cell lines All cell lines employed in this study robustly expressed the insulin receptor, and differences in insulin receptor expression between cell lines did not correlate with obesity association or lack thereof (Fig 1A)
To identify differences in tumor metabolism in obesity-related cancers, as opposed to obesityindependent cancers, we investigated substrate preference in three cell lines from obesity-associated cancer types, each of which exhibits accelerated tumor growth associated with obesity: MC38, a colon adenocarcinoma [19, 30, 48,49,50], 4TI, a triple-negative breast cancer [51, 52], and TRAMP-C3, a prostate adenocarcinoma [53]
Summary
Obesity is well-known to increase the prevalence and mortality of more than one dozen tumor types. Hyperinsulinemia has emerged as a focal point of research on obesity-related tumors, with increased plasma insulin concentrations independently predicting increased risk and mortality in prostate [1, 2], colon [3,4,5,6,7], breast [8,9,10,11,12,13], endometrial [12, 14, 15], and pancreatic cancer [16, 17], as well as several other tumor types. Obesity-associated tumors increase glucose oxidation in response to insulin
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