Work

UGDH promotes 5-fluorouracil resistance in colorectal cancer via the ROS-activated PI3K/AKT-EEF1A2-PRDX1 pathway

Year: 2025

Type: article

Abstract: 5-Fluorouracil (5-FU) chemotherapy resistance is a critical determinant of poor prognosis in patients with colorectal cancer (CRC). One critical mechanism underlying this resistance is the clearance of reactive oxygen species (ROS) generated by 5-FU, which diminishes its cytotoxic efficacy. Here, we identified the differential expression of UDP-glucose dehydrogenase (UGDH) in resistant cells through sequencing, and downstream targets EEF1A2 and PRDX1 were identified via immunoprecipitation-mass spectrometry (IP-MS). Stable knockdown and overexpression cell models were generated using a lentiviral system. The effects of gene manipulation on 5-FU resistance in CRC were evaluated both in vitro and in vivo through flow cytometry for reactive oxygen species (ROS) and apoptosis, as well as TUNEL immunofluorescence assays. Sequencing was utilized to enrich the relevant pathways. Our study firstly demonstrates that ROS-induced activation of the PI3K/AKT signaling pathway upregulates UGDH expression. UGDH promotes 5-FU resistance by collaborating with downstream effectors EEF1A2 and PRDX1 to clear ROS and inhibit tumor cell apoptosis. UGDH serves as a potential biomarker for 5-FU resistance in CRC, with its expression levels providing a crucial basis for therapeutic decision-making. • UGDH Drives 5-FU Resistance. o UGDH is upregulated in 5-FU-resistant CRC cells and promotes chemoresistance by scavenging ROS and inhibiting apoptosis. •ROS-PI3K/AKT-UGDH Feedback Loop o 5-FU-induced ROS activates PI3K/AKT signaling, which transcriptionally upregulates UGDH, forming a survival-promoting feedback loop. •UGDH-EEF1A2-PRDX1 Antioxidant Axis o UGDH interacts with EEF1A2 to enhance PRDX1 translation, enabling efficient ROS clearance and cell survival. •In Vivo Validation o UGDH knockdown sensitizes CRC xenografts to 5-FU, reducing tumor growth and increasing apoptosis. •Clinical Relevance o UGDH is downregulated in CRC tissues but dynamically induced by chemotherapy, serving as a potential biomarker for personalized therapy.

Source: Archives of Biochemistry and Biophysics

DOI: 10.1016/j.abb.2025.110445