title: Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma.
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.
authors: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors: Niamh
authors: N
authors: Lynam-Lennon
authors: Department of Surgery, Trinity College Dublin, Dublin, Ireland; Cancer Biology and Therapeutics Lab, School of Biological, Biomedical and Environmental Sciences, University of Hull, Hull, United Kingdom.
authors: Stephen G
authors: SG
authors: Maher
authors: Department of Pathology, St James's Hospital, Dublin, Ireland.
authors: Aoife
authors: A
authors: Maguire
authors: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors: James
authors: J
authors: Phelan
authors: Department of Pathology, St James's Hospital, Dublin, Ireland.
authors: Cian
authors: C
authors: Muldoon
authors: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors: John V
authors: JV
authors: Reynolds
authors: Department of Surgery, Trinity College Dublin, Dublin, Ireland.
authors: Jacintha
authors: J
authors: O'Sullivan
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D059186:Chemoradiotherapy, Adjuvant; D004734:Energy Metabolism / Q000187:drug effects / Q000528:radiation effects*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D053142:Mitochondrial Size / Q000187:drug effects / Q000528:radiation effects; D016296:Mutagenesis / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects; D016896:Treatment Outcome