Abstract
415 Background: Overcoming drug resistance in colorectal cancer (CRC) involves understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established a model of oxaliplatin resistant cells derived from HCT116/HT29 (HCT116 OxR/HT29 OxR). How these resistant clones reprogram their energy metabolism to gain a survival advantage remains unknown. We hypothesized that chemoresistant CRC cells exhibit altered cellular metabolism to survive following chronic genotoxic stress. Methods: The expression levels of glycolytic enzymes were detected by Western Blotting. Glucose and lactate concentrations were measured in the culturing media (CM). Intracellular ATP/ADP levels, oxygen consumption rate (OCR) and mitochondria ATP production were measured. In vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells. Results: Both HT29-OxR and HCT116-OxR cells compared to parental cells exhibit increased aerobic glycolysis. Consistently, Glut1, Hexokinase 2 and LDHA glycolytic enzymes are upregulated. The OxR cells are defective in mitochondria complex I/II substrate and ATP production despite increased OCR. Importantly, the OXR cells maintain higher intracellular ATP and ATP/ADP ratio, increased HIF1a and VEGF levels in the CM. In tumor xenograft model, HT29 OxR cells grow significant slower than parental HT29 cells. Interestingly, when OxR cells were mixed with parental HT29 cells (50:50 and 90:10), tumor growth and microvessel counts were significantly accelerated. Conclusions: OxR cells demonstrate: 1) high aerobic glycolytic activity; 2) defective mitochondria functions; 3) increased ATP production; 4) increased HIF1a and angiogenesis. Likely, this metabolic switch contributes to the resistant phenotype. Metabolism intervention such as targeting HIF1a may provide a novel strategy to overcome drug-resistance in CRC. No significant financial relationships to disclose.
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