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Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Lynam-Lennon, Niamh; Maher, Stephen G.; Maguire, Aoife; Phelan, James; Muldoon, Cian; Reynolds, John V.; O'Sullivan, Jacintha


Niamh Lynam-Lennon

Stephen G. Maher

Aoife Maguire

James Phelan

Cian Muldoon

John V. Reynolds

Jacintha O'Sullivan


Roberto Amendola


Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC.


Lynam-Lennon, N., Maher, S. G., Maguire, A., Phelan, J., Muldoon, C., Reynolds, J. V., & O'Sullivan, J. (2014). Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma. PLoS ONE, 9(6), e100738.

Journal Article Type Article
Acceptance Date May 30, 2014
Online Publication Date Jun 26, 2014
Publication Date Jun 26, 2014
Deposit Date Aug 14, 2015
Publicly Available Date Nov 23, 2017
Journal PLoS one
Print ISSN 1932-6203
Electronic ISSN 1932-6203
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 9
Issue 6
Article Number ARTN e100738
Pages e100738
Keywords Mitochondria, Energy metabolism, Cell metabolism, Oxidative phosphorylation, Cancer treatment, Glycolysis, Biopsy, Epithelium
Public URL
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Published article (2.7 Mb)

Copyright Statement
© 2014 Lynam-Lennon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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