Targeting the AURKB-MAD2L2 Axis Disrupts the DNA Damage Response and Glycolysis to Inhibit Colorectal Cancer Progression

Dysregulated metabolic pathways, including glycolysis and a compromised DNA damage response (DDR), are linked to the progression of colorectal cancer (CRC). The mitotic arrest deficient-like 2 (MAD2L2) and aurora kinase B (AURKB) genes play roles in cell cycle regulation and the DDR, making them potential targets for CRC therapy. Differential expression analysis was performed using The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) and GSE47074 datasets. A predictive model was established, and gene expression levels were further analyzed. The Gene Expression Profiling Interaction Analysis database and co-immunoprecipitation experiments assessed the correlation between AURKB and MAD2L2. Knockdown experiments in CRC cell lines further investigated the role of AURKB, followed by analyses of cell behavior, oxidative stress, glycolysis, DDR, and interaction with MAD2L2. The risk model identified six prognostic genes (BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), AURKB, aurora kinase A (AURKA), exonuclease 1 (EXO1), topoisomerase II alpha (TOP2A), cyclin A2 (CCNA2)) associated with CRC, which were significantly expressed in tumor samples from the TCGA-COAD and GSE47074 datasets. In vitro assays confirmed that AURKB knockdown inhibited CRC cell behavior, induced G1 cell cycle arrest, and increased oxidative stress and apoptosis. AURKB knockdown also impaired glycolysis, reducing lactate production, glucose uptake, and ATP levels. Overexpression of MAD2L2 partially reversed these effects, restored glycolytic activity, and mitigated the cell cycle arrest and DDR caused by AURKB knockdown. AURKB regulates CRC progression by modulating glycolysis and DDR pathways. Targeting the AURKB-MAD2L2 axis offers a promising therapeutic strategy for disrupting fundamental metabolic and DNA repair mechanisms in CRC.