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Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma.

Lynam-Lennon N, Connaughton R, Carr E, Mongan AM, O'Farrell NJ, Porter RK, Brennan L, Pidgeon GP, Lysaght J, Reynolds JV, O'Sullivan J - BMC Cancer (2014)

Bottom Line: ACM 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. osullij4@tcd.ie.

ABSTRACT

Background: Visceral 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.

Methods: Adipose 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.

Results: ACM 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.

Conclusion: This 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.

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PKM2expression in EAC tumors is associated with obesity. Gene expression profiling was performed on 29 EAC tumor biopsies by qPCR. (A) PKM2 expression was significantly positively associated with BMI. (B) ATP5B expression was not associated with BMI. Analysis was performed using linear regression.
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Fig5: PKM2expression in EAC tumors is associated with obesity. Gene expression profiling was performed on 29 EAC tumor biopsies by qPCR. (A) PKM2 expression was significantly positively associated with BMI. (B) ATP5B expression was not associated with BMI. Analysis was performed using linear regression.

Mentions: Supporting the obese ACM-induced increase in glycolysis in EAC cells demonstrated in vitro, expression of PKM2 was significantly positively associated with BMI in EAC tumor biopsies (R = 0.398, p = 0.049, Figure 5A). There was no significant association between expression of the oxidative phosphorylation marker ATP5B and BMI in EAC tumor biopsies (Figure 5B). This supports our in vitro data and suggests that alterations in tumor energy metabolism, specifically enhanced glycolysis, is associated with obesity in EAC patients.Figure 5


Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma.

Lynam-Lennon N, Connaughton R, Carr E, Mongan AM, O'Farrell NJ, Porter RK, Brennan L, Pidgeon GP, Lysaght J, Reynolds JV, O'Sullivan J - BMC Cancer (2014)

PKM2expression in EAC tumors is associated with obesity. Gene expression profiling was performed on 29 EAC tumor biopsies by qPCR. (A) PKM2 expression was significantly positively associated with BMI. (B) ATP5B expression was not associated with BMI. Analysis was performed using linear regression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4265417&req=5

Fig5: PKM2expression in EAC tumors is associated with obesity. Gene expression profiling was performed on 29 EAC tumor biopsies by qPCR. (A) PKM2 expression was significantly positively associated with BMI. (B) ATP5B expression was not associated with BMI. Analysis was performed using linear regression.
Mentions: Supporting the obese ACM-induced increase in glycolysis in EAC cells demonstrated in vitro, expression of PKM2 was significantly positively associated with BMI in EAC tumor biopsies (R = 0.398, p = 0.049, Figure 5A). There was no significant association between expression of the oxidative phosphorylation marker ATP5B and BMI in EAC tumor biopsies (Figure 5B). This supports our in vitro data and suggests that alterations in tumor energy metabolism, specifically enhanced glycolysis, is associated with obesity in EAC patients.Figure 5

Bottom Line: ACM 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland. osullij4@tcd.ie.

ABSTRACT

Background: Visceral 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.

Methods: Adipose 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.

Results: ACM 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.

Conclusion: This 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.

Show MeSH
Related in: MedlinePlus