Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:69691-69708. https://doi.org/10.18632/oncotarget.18883

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Abstract

Eun Hee Han1,2,6,*, Jin-Young Min1,3,*, Shin-Ae Yoo1, Sung-Joon Park1, Yun-Jeong Choe1,2, Hee Sub Yun1, Zee-Won Lee1, Sun Woo Jin4, Hyung Gyun Kim4, Hye Gwang Jeong4, Hyun Kyoung Kim5, Nam Doo Kim5 and Young-Ho Chung1,3,6

1Drug & Disease Target Research Team, Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, South Korea

2Immunotherapy Convergence Research Center, Korean Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, South Korea

3Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon 34134, South Korea

4Department of Toxicology, College of Pharmacy, Chungnam National University (CNU), Daejeon 34133, South Korea

5New Drug Development Center, Daugu Gyeoungbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea

6Department of Bioanalytical Science, Korea University of Science and Technology (UST), Daejeon 34113, South Korea

*These authors have contributed equally to this work

Correspondence to:

Young-Ho Chung, email: [email protected]

Keywords: AURKC, protein–protein interaction, IκBα, small-molecule inhibitor, breast cancer

Received: December 29, 2016     Accepted: June 05, 2017     Published: June 29, 2017

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.


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