Targeting Aurora-A Inhibits Tumor Progression and Sensitizes Thyroid Carcinoma to sorafenib by decreasing PFKFB3-mediated glycolysis

Abstract

Background Thyroid cancer (TC) is the most common endocrine tumor, amongst which anaplastic thyroid carcinoma (ATC) is the most deadly. Aurora-A usually functions as oncogenes, and its inhibitor Alisertib exerts a powerful antitumor effect in various tumors. However, the mechanism of Aurora-A in regulating TC cell energy supply remains unclear. Methods Phosphoproteome and proteome analyses and RNA-seq were performed to investigate the molecular mechanisms of Aurora-A-induced tumor cell progression, which were further verified by in vitro modulations of Aurora-A and related pathways. An immunohistochemistry assay was carried out to evaluate the relationship between Aurora-A and patient prognosis. Finally, the antitumor efficacy of the Alisertib/Sorafenib combination was assessed in vitro and in vivo. Results We demonstrated the antitumor effect of Alisertib and an association between high Aurora-A expression and shorter survival. Multi-omics data and in vitro validation data suggested that Aurora-A induced PFKFB3-mediated glycolysis to increase ATP supply, which significantly upregulated the phosphorylation of ERK and AKT. The combination of Alisertib and Sorafenib had a synergistic effect, further confirmed in xenograft models and in vitro. Conclusions We provide compelling evidence of the prognostic value of Aurora-A expression and suggest that Aurora-A upregulates PFKFB3-mediated glycolysis to enhance ATP supply and promote TC progression. Combining Alisertib with Sorafenib has huge prospects for application in treating advanced thyroid carcinoma.