Energy Metabolism Is Altered in Radioresistant Rectal Cancer

Abstract

Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients.

Metformin is a metabolic modulator and radiosensitiser in rectal cancer

“…We and others have previously characterised these in vitro models of CRC, demonstrating SW837 rectal cells as a robust model of radioresistant rectal cancer (23,48,49). We have previously demonstrated that SW837 cells have a reduced reliance on glycolysis, supporting a role for enhanced mitochondrial metabolism in the radioresistance of these cells (23). In this study, metformin was demonstrated to significantly inhibit oxidative phosphorylation and enhance glycolytic rates in both HCT116 and SW837 cells, supporting it as an ETC inhibitor in CRC.…”

“…In this study, SW837 rectal cancer cells, and HCT116 colon cancer cells were utilised as an in vitro model of inherently radioresistant, and radiosensitive CRC, respectively. We and others have previously characterised these in vitro models of CRC, demonstrating SW837 rectal cells as a robust model of radioresistant rectal cancer (23,48,49). We have previously demonstrated that SW837 cells have a reduced reliance on glycolysis, supporting a role for enhanced mitochondrial metabolism in the radioresistance of these cells (23).…”

“…Increasing evidence supports a role for altered energy metabolism in the radioresistance of cancer (18)(19)(20). We have previously demonstrated that metabolic reprogramming is associated with a radioresistant phenotype in both in vitro and ex vivo models of oesophageal adenocarcinoma (21,22) and rectal adenocarcinoma (23).…”

“…Having demonstrated metformin-mediated inhibition of oxidative phosphorylation in both HCT116 and SW837 cells, the potential of metformin as a radiosensitiser in vitro was investigated. We and others have previously identified SW837 rectal cancer and HCT116 colon cancer cells as an in vitro model of inherently radioresistant, and radiosensitive CRC, respectively (23,33). The potential radiosensitising effects of metformin (1 mM, 2.5 mM, 10 mM) following a clinicallyrelevant dose of 1.8 Gy X-ray radiation was assessed in HCT116 and SW837 cells using the gold standard clonogenic assay.…”

“…Increasing evidence supports a role for altered metabolism in the tumour response to treatment (18,21,22,(35)(36)(37)(38)(39)(40)(41). We have previously demonstrated that enhanced oxidative phosphorylation and reduced dependence on glycolysis is associated with a radioresistant phenotype in oesophageal adenocarcinoma (21,22) and rectal adenocarcinoma (23), respectively, suggesting that targeting energy metabolism, specifically oxidative phosphorylation, may be an effective strategy to enhance therapeutic response to neoCRT (42).…”