A small-molecule inhibitor targeting the AURKC-I?B? interaction decreases transformed growth of MDA-MB-231 breast cancer cells.
Ontology highlight
ABSTRACT: 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?B? as a binding partner of AURKC, and found that AURKC phosphorylates I?B? at Ser32, thereby activating it. In silico modeling and computational analyses revealed a small-molecule inhibitor (AKCI) that blocked the AURKC-I?B? 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?B?, AURKC indirectly induced NF-?B activation; accordingly, AKCI decreased PMA-induced activation of NF-?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.
SUBMITTER: Han EH
PROVIDER: S-EPMC5642509 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
ACCESS DATA