Abstract
BackgroundVisceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Alterations in mitochondrial function and energy metabolism is an emerging hallmark of cancer, however, the potential role that obesity plays in driving these alterations in EAC is currently unknown.MethodsAdipose conditioned media (ACM) was prepared from visceral adipose tissue taken from computed tomography-determined viscerally-obese and non-obese EAC patients. Mitochondrial function in EAC cell lines was assessed using fluorescent probes, mitochondrial gene expression was assessed using qPCR-based gene arrays and intracellular ATP levels were determined using a luminescence-based kit. Glycolysis and oxidative phosphophorylation was measured using Seahorse XF technology and metabolomic analysis was performed using 1H NMR. Expression of metabolic markers was assessed in EAC tumor biopsies by qPCR.ResultsACM from obese EAC patients significantly increased mitochondrial mass and mitochondrial membrane potential in EAC cells, which was significantly associated with visceral fat area, and was coupled with a significant decrease in reactive oxygen species. This mitochondrial dysfunction was accompanied by altered expression of 19 mitochondrial-associated genes and significantly reduced intracellular ATP levels. ACM from obese EAC patients induced a metabolic shift to glycolysis in EAC cells, which was coupled with significantly increased sensitivity to the glycolytic inhibitor 2-deoxyglucose. Metabolomic profiling demonstrated an altered glycolysis and amino acid-related signature in ACM from obese patients. In EAC tumors, expression of the glycolytic marker PKM2 was significantly positively associated with obesity.ConclusionThis study demonstrates for the first time that ACM from viscerally-obese EAC patients elicits an altered metabolic profile and can drive mitochondrial dysfunction and altered energy metabolism in EAC cells in vitro. In vivo, in EAC patient tumors, expression of the glycolytic enzyme PKM2 is positively associated with obesity.
Highlights
Visceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC)
Adipose conditioned media (ACM) from viscerally-obese EAC patients induces mitochondrial dysfunction To investigate the effect of obesity on mitochondrial function in EAC, OE33 EAC cells were incubated with ACM generated from viscerally obese (n = 5) and nonobese EAC patients (n = 5) or M199 control media for 24 h
Tumor-derived expression of Pyruvate Kinase M2 (PKM2) is significantly associated with obesity Given the demonstrated ACM-induced alterations in both mitochondrial function and energy metabolism in EAC cells in vitro, we investigated if metabolic alterations in EAC patient tumors were associated with obesity
Summary
Visceral obesity has a strong association with both the incidence and mortality of esophageal adenocarcinoma (EAC). Mitochondria are functionally altered in tumors [12] and are involved in metabolic reprogramming known as the “Warburg effect’, which describes the shift of cancer cells from oxidative phosphorylation to glycolysis [13]. This metabolic shift facilitates rapidly proliferating cells and is implicated in both the initiation and progression of cancer [14]. Multiple hallmarks of cancer, including evasion of apoptosis, unlimited proliferative potential and invasion have been linked directly or indirectly with mitochondrial alterations [12], highlighting alterations in mitochondrial function and energy metabolism as a potential mechanism by which obesity may promote tumorigenesis
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