A small-molecule inhibitor targeting the AURKC-IκBα interaction decreases transformed growth of MDA-MB-231 breast cancer cells

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 IκBα as a binding partner of AURKC, and found that AURKC phosphorylates IκBα at Ser32, thereby activating it. In silico modeling and computational analyses revealed a small-molecule inhibitor (AKCI) that blocked the AURKC–IκBα 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 IκBα, AURKC indirectly induced NF-κB activation; accordingly, AKCI decreased PMA-induced activation of NF-κB. 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.

Mitochondria-targeted antioxidant SkQ1 suppresses fibrosarcoma and rhabdomyosarcoma tumour cell growth

“…Aurora C is expressed in germ cells, playing a role in meiosis analogous to Aurora B in mitosis [35]. Aurora C contributes to breast cancer cell transformation, but its role in carcinogenesis is still unclear [36]. Our data confirms the regulatory function of Aurora C in mitosis of cells with activated N-RAS oncogene.…”

Co-relation with novel phosphorylation sites of IκBα andnecroptosis in breast cancer cells

“…IκBα is phosphorylated by protein-protein interactions between IκBα and AURK. [5,17] AURK also regulates cell cycle and cell division. To suppress the proliferation of cancer cells, more powerful inhibition of IκBα is required, and thus, IκBα activity is controlled through AURK.…”

“…In a previous study [17], the interaction between IκBα and AurkC was identi ed using the CUPID system. The result was demonstrated through typical experiments, including co-immunoprecipitation and use of a mammalian two-hybrid system.…”

“…and Aurora-C. AURKA and AURKB are involved in mitosis (cell division producing identical daughter cells), and AURKC is involved in meiosis (sexual reproduction). [14,15] This proteins is over-expressed in various cancer cell lines such as breast cancer, [16,17] suggesting an involvement in oncogenic signal transduction. [17] In the study reported here, MALDI-TOF MS and nanoLC-quadrupole orbitrap MS/MS were used to obtain sequence data on IκBα phosphorylated in vitro by AURK, and identi cation of biological process by novel phosphorylation site.…”

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

“…AURKA, is a type of Aurora kinases. Recently, several Au0072ora kinase inhibitors were being investigated as novel anticancer therapy in breast cancer [33] . The importance of AURKA in ALL has not been studied deeply, our analysis will provide a new angle for further investigation.…”