Abstract 4075: Chemoresistant colorectal cancer cells exhibit high glycolytic activity

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Overcoming drug resistance in colorectal cancer (CRC) requires an understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established oxaliplatin resistant CRC cells derived from HCT116 and HT29 cell lines (HCT116 OxR and HT29 OxR) (Yang AD et al, Clin Ca Res, 2007). The mechanisms by which these resistant clones reprogram their energy metabolism to gain a survival advantage remain unknown. In this study, we hypothesized that chemoresistant CRC cells would exhibit altered cellular metabolism in order to survive following chronic genotoxic stress. Methods: The expression level of the glycolytic enzymes Glut1, hexokinase II (HK2), LDHA and HIF1α were detected by Western Blotting. Glucose uptake and lactate production was calculated by measuring the concentration of glucose and lactate in the culture media. Intracellular ATP/ADP levels, oxygen consumption and mitochondria ATP production were quantified. An in vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells. Results: Compared with the parental cells, both HT29-OxR and HCT116-OxR cells exhibited a metabolic phenotype with increased glycolysis as reflected by increased glucose uptake and lactate production. Glycolytic enzymes were upregulated in resistant cells including Glut1, HK2 and LDHA. HIF1α expression and VEGF levels in the conditioned media were increased in the resistant cells. The mitochondria of OxR cells demonstrated defective complex I/II substrate ATP production despite increased cellular oxygen consumption. Importantly, the OxR cells maintain higher levels of intracellular ATP and ATP/ADP ratio indicating a metabolic switch to glycolysis. In a tumor xenograft model, HT29 OxR cells grew significantly 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 increased. Conclusion: Oxaliplatin-resistant cells demonstrated: 1) high aerobic glycolytic activity, 2) an increase in HIF1α and glycolytic enzymes, and 3) defective mitochondria function. This metabolic switch provides more ATP production and likely contributes to the chemoresistant phenotype. Altering energy metabolism may provide a novel strategy to overcome drug-resistance in CRC cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4075. doi:10.1158/1538-7445.AM2011-4075