The AURKA-PTTG1 signaling axis induces enzalutamide resistance in prostate cancer.

BACKGROUND: Prostate cancer (PCa), a common male malignant tumor, often develops resistance to the androgen receptor inhibitor enzalutamide (ENZ). Despite its established oncogenic role, pituitary tumor-transforming gene 1 (PTTG1)'s specific function and regulatory mechanism in ENZ-resistant PCa require investigation. METHODS: Cell biology assays were employed to evaluate the effects of PTTG1 and Aurora kinase A (AURKA) on cell proliferation, apoptosis, migration, and ENZ resistance. Bioinformatics analysis revealed that the glycolytic signaling pathway was significantly enriched in the PTTG1‑high expression group. Subsequently, the regulatory roles of PTTG1 and AURKA in glycolysis were verified by measuring glycolysis‑related metabolic parameters and changes in the expression of key proteins. The physical interaction between PTTG1 and AURKA was confirmed by predictions from protein-protein interaction databases and validated by co‑immunoprecipitation experiments. After determining the subcellular localization of PTTG1 through cell fractionation assays, we further assessed the effect of AURKA on the serine phosphorylation levels of the purified GFP-PTTG1 fusion protein. All in vitro results were validated in a nude mouse xenograft model using immunofluorescence, immunohistochemistry, and apoptosis detection assays. RESULTS: In ENZ-resistant PCa cells, PTTG1 was highly expressed, and its phosphorylation was promoted by AURKA, which in turn facilitated its nuclear translocation to activate Wnt signaling and glycolytic metabolism, driving ENZ resistance in PCa. Targeting the AURKA/PTTG1 axis enhanced ENZ sensitivity in a PCa mouse model. CONCLUSION: The AURKA/PTTG1 axis contributes to ENZ resistance by promoting glycolytic metabolism in PCa cells.