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

Hdl Handle:
http://hdl.handle.net/10147/559471
Title:
Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma
Authors:
Lynam-Lennon, Niamh; Connaughton, Ruth; Carr, Eibhlin; Mongan, Ann-Marie; O’Farrell, Naoimh J; Porter, Richard K; Brennan, Lorraine; Pidgeon, Graham P; Lysaght, Joanne; Reynolds, John V; O’Sullivan, Jacintha
Citation:
BMC Cancer. 2014 Dec 03;14(1):907
Issue Date:
3-Dec-2014
URI:
http://dx.doi.org/10.1186/1471-2407-14-907; http://hdl.handle.net/10147/559471
Abstract:
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.
Language:
en
Keywords:
CANCER, OESOPAHGEAL; OBESITY

Full metadata record

DC FieldValue Language
dc.contributor.authorLynam-Lennon, Niamhen
dc.contributor.authorConnaughton, Ruthen
dc.contributor.authorCarr, Eibhlinen
dc.contributor.authorMongan, Ann-Marieen
dc.contributor.authorO’Farrell, Naoimh Jen
dc.contributor.authorPorter, Richard Ken
dc.contributor.authorBrennan, Lorraineen
dc.contributor.authorPidgeon, Graham Pen
dc.contributor.authorLysaght, Joanneen
dc.contributor.authorReynolds, John Ven
dc.contributor.authorO’Sullivan, Jacinthaen
dc.date.accessioned2015-07-10T09:59:59Zen
dc.date.available2015-07-10T09:59:59Zen
dc.date.issued2014-12-03en
dc.identifier.citationBMC Cancer. 2014 Dec 03;14(1):907en
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2407-14-907en
dc.identifier.urihttp://hdl.handle.net/10147/559471en
dc.description.abstractAbstract 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.-
dc.language.isoenen
dc.subjectCANCER, OESOPAHGEALen
dc.subjectOBESITYen
dc.titleExcess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinomaen
dc.language.rfc3066en-
dc.rights.holderNiamh Lynam-Lennon et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2014-12-11T20:40:29Z-
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