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

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.

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. https://doi.org/10.1371/journal.pone.0100738

• 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
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 6
• Article Number: ARTN e100738
• Pages: e100738
• DOI: https://doi.org/10.1371/journal.pone.0100738
• Keywords: Mitochondria, Energy metabolism, Cell metabolism, Oxidative phosphorylation, Cancer treatment, Glycolysis, Biopsy, Epithelium
• Public URL: https://hull-repository.worktribe.com/output/377675
• Publisher URL: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100738
• Contract Date: Nov 23, 2017