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

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

Authors

Jacintha O’Sullivan

Niamh Lynam-Lennon

Stephen G. Maher

Aoife Maguire

James Phelan

Cian Muldoon

John V. Reynolds

Jacintha O'Sullivan



Contributors

Roberto Amendola
Editor

Abstract

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.

Journal Article Type Article
Publication Date Jun 26, 2014
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
Institution Citation 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. doi:10.1371/journal.pone.0100738
DOI https://doi.org/10.1371/journal.pone.0100738
Keywords Mitochondria, Energy metabolism, Cell metabolism, Oxidative phosphorylation, Cancer treatment, Glycolysis, Biopsy, Epithelium
Publisher URL http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100738
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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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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