A small-molecule inhibitor targeting the AURKC-I kappa B alpha interaction decreases transformed growth of MDA-MB-231 breast cancer cells

作者：Han Eun Hee; Min Jin Young; Yoo Shin Ae; Park Sung Joon; Choe Yun Jeong; Yun Hee Sub; Lee Zee Won; Jin Sun Woo; Kim Hyung Gyun; Jeong Hye Gwang; Kim Hyun Kyoung; Kim Nam Doo; Chung Young Ho

来源：Oncotarget, 2017, 8(41): 69691-69708.

DOI：10.18632/oncotarget.18883

• AURKC
• protein-protein interaction
• I kappa B alpha
• small-molecule inhibitor
• breast cancer

The Aurora kinases, Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) or meiosis (AURKC). Several Aurora kinase inhibitors are being investigated as novel anticancer therapeutics. Recent studies demonstrated that AURKC activation contributes to breast cancer cell transformation. Therefore, AURKC is both a promising marker and therapeutic target for breast cancer; however, its signaling network has not been fully characterized. Using translocation-based cellular assays, we identified I kappa B alpha as a binding partner of AURKC, and found that AURKC phosphorylates I kappa B alpha at Ser32, thereby activating it. In silico modeling and computational analyses revealed a small-molecule inhibitor (AKCI) that blocked the AURKC-I kappa B alpha interaction and exerted antitumor activity in MDA-MB-231 breast cancer cells. Specifically, AKCI induced G2/M cell-cycle arrest through modulation of the p53/p21/CDC2/cyclin B1 pathways. In addition, the drug significantly inhibited MDA-MB-231 cell migration and invasion, as well as decreasing colony formation and tumor growth. Via its interaction with I kappa B alpha, AURKC indirectly induced NF-kappa B activation; accordingly, AKCI decreased PMA-induced activation of NF-kappa B. Thus, the small-molecule inhibitor AKCI represents a first step towards developing targeted inhibitors of AURKC protein binding, which may lead to further advances in the treatment of breast cancer.

• 出版日期2017-9-19