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Bisphenol A Promotes the Progression of Colon Cancer Through Dual-Targeting of NADPH Oxidase and Mitochondrial Electron-Transport Chain to Produce ROS and Activating HIF-1α/VEGF/PI3K/AKT Axis.

ABSTRACT: Bisphenol A (BPA) is a high-production-volume industrial chemical. Despite recent research conducted on its carcinogenicity, its role in the development of colon cancer (CC) has been rarely studied. This study aims to evaluate the effects of BPA on the migration and invasion of CC cells. First, we clinically verified that patients with CC exhibit higher serum BPA level than healthy donors. Subsequently, different CC cell lines were exposed to a series of BPA concentrations, and the migration and invasion of cells were detected by the wound healing test and transwell assay. Finally, N-acetyl-L-cysteine (NAC) and siHIF-1α intervention was used to explore the effects of ROS and HIF-1α on cell migration and invasion, respectively. The results demonstrated that the occurrence of BPA-induced migration and invasion were dependent on the dose and time and was most pronounced in DLD1 cells. ROS production was jointly driven by NADPH oxidase (NOX) and mitochondrial electron-transport chain (ETC). Furthermore, the intervention of NAC and siHIF-1α blocked the HIF-1α/VEGF/PI3K/AKT axis and inhibited cell migration and invasion. In conclusion, our results suggest that BPA exposure promotes the excessive production of ROS induced by NOX and ETC, which in turn activates the HIF-1α/VEGF/PI3K/AKT axis to promote the migration and invasion of CC cells. This study provides new insights into the carcinogenic effects of BPA on CC and warns people to pay attention to environmental pollution and the harm caused to human health by low-dose BPA.

SUBMITTER: Xia T

PROVIDER: S-EPMC9289207 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcquired 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.MethodsThree separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.ResultsThe abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines 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 occurred 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.ConclusionsHIF-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.

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Bisphenol A Promotes the Progression of Colon Cancer Through Dual-Targeting of NADPH Oxidase and Mitochondrial Electron-Transport Chain to Produce ROS and Activating HIF-1α/VEGF/PI3K/AKT Axis.

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