Abstract
Obesity creates a localized inflammatory reaction in the adipose, altering secretion of adipocyte-derived factors that contribute to pathologies including cancer. We have previously shown that adiponectin inhibits pancreatic cancer by antagonizing leptin-induced STAT3 activation. Yet, the effects of adiponectin on pancreatic cancer cell metabolism have not been addressed. In these studies, we have uncovered a novel metabolic function for the synthetic adiponectin-receptor agonist, AdipoRon. Treatment of PDAC cells with AdipoRon led to mitochondrial uncoupling and loss of ATP production. Concomitantly, AdipoRon-treated cells increased glucose uptake and utilization. This metabolic switch further correlated with AMPK mediated inhibition of the prolipogenic factor acetyl coenzyme A carboxylase 1 (ACC1), which is known to initiate fatty acid catabolism. Yet, measurements of fatty acid oxidation failed to detect any alteration in response to AdipoRon treatment, suggesting a deficiency for compensation. Additional disruption of glycolytic dependence, using either a glycolysis inhibitor or low-glucose conditions, demonstrated an impairment of growth and survival of all pancreatic cancer cell lines tested. Collectively, these studies provide evidence that pancreatic cancer cells utilize metabolic plasticity to upregulate glycolysis in order to adapt to suppression of oxidative phosphorylation in the presence of AdipoRon.
Highlights
With regard to pancreatic cancer, we demonstrated that the effects of adiponectin and AdipoRon on cancer cells were partially due to suppression of the STAT3 signaling pathway as well
Our previous study reported that adiponectin as well as its receptor mimetic, AdipoRon, can effectively inhibit proliferation and induce apoptosis in pancreatic cancer cell lines, albeit at concentrations greater than 25 μM [10]
We demonstrated that the effects of adiponectin and AdipoRon on cancer cells were due, in part, to suppression of the STAT3 signaling pathway as well as AMPKpathway activation [10, 12]
Summary
Pancreatic cancer is the fourth leading cause of cancer death with a dismal five year survival rate of 9% [1]. Other studies showed that AMPK activation in AdipoRon treatment decreased the OCR (Fig. 2A), basal and response to AdipoRon correlated with a suppression of insulin maximal respiration (Fig. 2B, C), ATP production (Fig. 2D) and resistance and glucose intolerance [22], highlighting a metabolic proton leak (Fig. 2E) while increasing mitochondrial uncoupling therapeutic potential for AdipoRon. The results support a modulatory role for AdipoRon on altered ECAR response in all six PDAC cells tested (Fig. 3A), the metabolic phenotype of pancreatic cancer and further correlating with increased glycolysis (Fig. 3B), suggesting a demonstrate that dual metabolic targeting of glycolysis in compensatory response to the defective mitochondrial ATP conjugation with AdipoRon may provide an effective antiproli- production. Of the six cell lines tested, while no significant change in glycolytic capacity was noted in the other four cell lines (Fig. 3C)
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