A Novel Anti-Cancer Agent, 1-(3,5-Dimethoxyphenyl)-4-[(6-Fluoro-2-Methoxyquinoxalin-3-yl)Aminocarbonyl] Piperazine (RX-5902), Interferes With β-Catenin Function Through Y593 Phospho-p68 RNA Helicase

• Published in: Journal of cellular biochemistry 2015-08, Vol.116 (8), p.1595-1601
• Main Authors: Kost, Gina Chun, Yang, Mi Young, Li, Liangwei, Zhang, Yinwei, Liu, Chia-yi, Kim, Deog Joong, Ahn, Chang-Ho, Lee, Young Bok, Liu, Zhi-Ren
• Format: Article
• Language: English
• Subjects: ANTI-CANCER; Antineoplastic Agents - pharmacology; beta Catenin - metabolism; Binding; Binding Sites - drug effects; Cancer; Catenin; Cell Line, Tumor; Cyclin D1; DEAD-box RNA Helicases - chemistry; DEAD-box RNA Helicases - metabolism; DNA helicase; Gene expression; Humans; Myc protein; Neoplasms - drug therapy; Neoplasms - metabolism; p68 RNA HELICASE; PHOSPHO-p68; Phosphorylation; Piperazine; Piperazines - pharmacology; Protein Binding - drug effects; Quinoxalines - pharmacology; Ribonucleic acid; RNA; RNA helicase; RX-5902; Signal Transduction - drug effects; Tumor cell lines
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.25113

ABSTRACT 1‐(3,5‐Dimethoxyphenyl)‐4‐[(6‐fluoro‐2‐methoxyquinoxalin‐3‐yl)aminocarbonyl] piperazine (RX‐5902) exhibits strong growth inhibition in various human cancer cell lines with IC50 values ranging between 10 and 20 nM. In this study, we demonstrate that p68 RNA helicase is a cellular target of RX‐5902 by the drug affinity responsive target stability (DARTS) method, and confirmed the direct binding of 3H‐labeled RX‐5902 to Y593 phospho‐p68 RNA helicase. We further demonstrated RX‐5902 inhibited the β‐catenin dependent ATPase activity of p68 RNA helicase in an in vitro system. Furthermore, we showed that treatment of cancer cells with RX‐5902 resulted in the downregulation of the expression of certain genes, which are known to be regulated by the β‐catenin pathway, such as c‐Myc, cyclin D1 and p‐c‐Jun. Therefore, our study indicates that the inhibition of Y593 phospho‐p68 helicase ‐ β‐catenin interaction by direct binding of RX‐5902 to Y593 phospho‐p68 RNA helicase may contribute to the anti‐cancer activity of this compound. J. Cell. Biochem. 116: 1595–1601, 2015. © 2015 Wiley Periodicals, Inc.