Abstract
Abstract Elevated expression of Aurora kinase-A oncoprotein is detected in a subset of human cancers across different organ sites. The mechanism(s) underlying over expression of the protein in cancer cells have not been well elucidated. This study demonstrates that inactivation of a novel mechanism of EF1A2 regulated PTEN-GSK3β-SCF complex mediated Aurora-A protein degradation pathway in S-G2 phases of mitosis leads to enhanced stability/steady state level of Aurora-A in cancer cells. EEF1A2 regulates interaction of Aurora-A with activated PTEN, GSK3β, Neddylated CUL1 and FBXW7, promoting ubiquitination mediated degradation of Aurora-A that is rescued in EEF1A2 knockdown cells. Ectopic expression of EEF1A2, on the other hand, enhances formation of the complex with GSK3β mediated inactivating phosphorylation and reduction in Aurora-A protein, recapitulating the S-G2 phase events. Genetic ablation of EEF1A2 and PTEN in both in vitro cell lines and in vivo mouse models validated the results. Aurora-A over expressing mouse models of mammary carcinoma and human breast cancer tissue samples also corroborated the findings. Therapeutic targeting of PTEN-GSK3β-AKT pathway may, therefore, be effective in treating a subset Aurora-A over expressing cancers. Citation Format: Warapen Treekitkarnmongkol, Luisa Maren Solis, Kazuharu Kai, Kaori Sasai, Ignacio I. Wistuba, Aysegul A. Sahin, Kwong K. Wong, Alastair M. Thompson, Yoshimi Jltsumori, Jonathan M. Lee, Lidong Qin, Tasneem Bawa-Khalfe, Roland Rad, Catherine M. Abbott, Hiroshi Katayama, Subrata Sen. Aurora-A is elevated in cancer cells due to inactivation of EF1A2-PTEN-GSK3b regulated late S-G2 phase specific degradation pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-095.
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