AURKB and circAURKB_288aa enhance Esophageal cancer drug resistance through inducing abnormal centrosome separation

• Published in: Biochemical pharmacology 2025-02, Vol.232, p.116691, Article 116691
• Main Authors: Lv, Hongzhen, Zhou, Jing, Qiu, Limin, Tang, Xiaozhu, Huang, Cheng
• Format: Article
• Language: English
• Subjects: AURKB; Chromosomal instability; circAURKB_288aa; Drug resistance; Esophageal cancer; Proliferation
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116691

[Display omitted] Esophageal cancer (EC) is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the western world occurring over the past few decades. Chromosome instability (CIN) is a major contributor to EC progression, drug resistance, relapse, and the development of intratumoral heterogeneity. This study revealed a striking elevation of AURKB expression in EC patients, with a strong correlation to poor clinical outcomes. AURKB overexpression promoted cellular proliferation and induced drug resistance in both cell culture and animal models. Conversely, genetic targeting of AURKB abrogated these effects. Mechanistically, enforced AURKB expression triggered CIN, a key driver of poor EC outcomes, primarily through CEP250 phosphorylation. Interestingly, we identified a novel circular form of AURKB (circAURKB_288aa) harboring the AURKB kinase domain and encoding a 288-amino acid protein. Elevated levels of circAURKB_288aa in EC peripheral blood samples mirrored poor patient outcomes and synergistically enhanced CIN alongside AURKB. Furthermore, EC cells were capable of secreting circAURKB_288aa, influencing tumor microenvironmental cells similarly to full-length AURKB protein. Notably, AURKB siRNA targeting the shared kinase domain of both AURKB and circAURKB_288aa significantly inhibited EC malignancy. Collectively, these findings establish AURKB and circAURKB_288aa as promising targets for EC prognosis and therapy.