ROS/PI3K/Akt and Wnt/β-Catenin Signalings Activate HIF-1α-Induced Metabolic Reprogramming to Impart 5-Fluorouracil Resistance in Colorectal Cancer
Abstract Background: Acquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.Methods: We generated three acquired 5-FU resistance CRC cell line models, and the detailed assessment of glucose metabolism was performed by in vitro and in vivo experiments, including glucose and lactate utilization, the RNA and protein expressions of glucose metabolism‐related enzymes, the changes of intermediate metabolites of glucose metabolite pool and so on. We detected the protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients by immunohistochemistry and immunofluorescence. Stably HIF1A knockdown in cell models were established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was detected in cell models in vivo and in vitro.Results: Here we describe the condition of abnormal glucose metabolism in 5-FU-resistant CRC in detail, and we demonstrate that the enhanced glycolysis and pentose phosphate pathway in CRC are associated with increased HIF-1α expression. We also show that HIF-1α-induced glucose metabolic reprogramming imparts 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cells and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurs through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling, and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU, indicating the potential efficacy of strategies targeting HIF-1α as an upstream glycolytic pathway regulator. Conclusions: Our results indicate HIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.