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

BMC Cancer

Niamh Lynam-Lennon¹  Ruth Connaughton⁴  Eibhlin Carr²  Ann-Marie Mongan¹  Naoimh J O’Farrell¹  Richard K Porter³  Lorraine Brennan²  Graham P Pidgeon¹  Joanne Lysaght¹  John V Reynolds¹  Jacintha O’Sullivan¹ 

[1] Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

[2] Institute of Food and Health, University College Dublin, Dublin, Ireland

[3] School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland

[4] Nutrigenomics Research Group, University College Dublin, Dublin, Ireland

关键词: Metabolomics;    Bioenergetics;    Mitochondrial dysfunction;    Obesity;   

Others  :  1117961
DOI  :  10.1186/1471-2407-14-907

 received in 2014-03-11, accepted in 2014-11-20,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Lynam-Lennon et al.; licensee BioMed Central Ltd.

【 图 表 】

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