Repurposing Doxycycline to Overcome High-Glucose-Induced Mitochondrial Biogenesis-Mediated Chemoresistance in...

Chemoresistance is a major contributor to treatment failure in most patients with cancer. Hyperglycaemia enhances chemoresistance in stage III colorectal cancer (CRC) patients, potentially through a mechanism involving c-Myc. Phospho-PGC-1α (p-PGC-1α), a transcription coactivator, regulates energy metabolism with c-Myc and is a key regulator of mitochondrial biogenesis. We hypothesised that high glucose (HG) promotes mitochondrial biogenesis by upregulating c-Myc and p-PGC-1α, thus enhancing chemoresistance in CRC cells, and that inhibiting mitochondrial biogenesis alleviates this chemoresistance. In vitro, HG significantly increased mitochondrial mass (p < 0.001), oxygen consumption rate (p < 0.001), cell migration (p < 0.05) and oxaliplatin resistance (p < 0.001) in LoVo and HCT116 cells. p-PGC-1α and COX4 protein expression were increased in the HG and oxaliplatin-resistance groups in LoVo and HCT116 cells (all p < 0.001) and decreased in the doxycycline group (p < 0.001). In vivo, doxycycline combined with oxaliplatin more notably reduced tumour volume than oxaliplatin alone in hyperglycaemic BALB/c nude mice (p < 0.05). c-Myc, p-PGC-1α and COX4 protein expression were significantly higher in tissues with CRC and hyperglycaemia who experienced relapse than in those with CRC and normoglycaemia who did not experience relapse (all p < 0.05). Overall, this study demonstrated that HG upregulates p-PGC-1α and COX4 expression to enhance oxaliplatin resistance by promoting mitochondrial biogenesis and indicates that doxycycline can overcome the chemoresistance induced by HG. Repurposing of doxycycline might reduce chemoresistance in hyperglycaemic CRC patients receiving adjuvant chemotherapy.