Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins

Autor:	Roberto N. De Guzman, Hao Liu, Jeffrey Aubé, Lan Lan, Ragul Gowthaman, Rebecca T. Marquez, Sarah Larsen, Liang Xu, Philip Gao, Steven A. Rogers, Jia Yu, Kristi L. Neufeld, Amber R. Smith, Xiaoqing Wu, John Karanicolas, Carl Appelman, Frank Y. Liu
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine Cancer Research Gossypolone Colorectal cancer Adenomatous polyposis coli RNA-binding protein Cell Apoptosis Nerve Tissue Proteins lcsh:RC254-282 Musashi Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Genetics medicine Animals Humans Biological Products biology Chemistry Gossypol Wnt signaling pathway RNA-Binding Proteins medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Xenograft Model Antitumor Assays 3. Good health Colon cancer Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Colonic Neoplasms Liposomes NUMB Cancer research PEGylation biology.protein Signal Transduction Research Article
Zdroj:	BMC Cancer, Vol 18, Iss 1, Pp 1-14 (2018) BMC Cancer
ISSN:	1471-2407
DOI:	10.1186/s12885-018-4704-z
Popis:	Background The Musashi (MSI) family of RNA-binding proteins is best known for the role in post-transcriptional regulation of target mRNAs. Elevated MSI1 levels in a variety of human cancer are associated with up-regulation of Notch/Wnt signaling. MSI1 binds to and negatively regulates translation of Numb and APC (adenomatous polyposis coli), negative regulators of Notch and Wnt signaling respectively. Methods Previously, we have shown that the natural product (−)-gossypol as the first known small molecule inhibitor of MSI1 that down-regulates Notch/Wnt signaling and inhibits tumor xenograft growth in vivo. Using a fluorescence polarization (FP) competition assay, we identified gossypolone (Gn) with a > 20-fold increase in Ki value compared to (−)-gossypol. We validated Gn binding to MSI1 using surface plasmon resonance, nuclear magnetic resonance, and cellular thermal shift assay, and tested the effects of Gn on colon cancer cells and colon cancer DLD-1 xenografts in nude mice. Results In colon cancer cells, Gn reduced Notch/Wnt signaling and induced apoptosis. Compared to (−)-gossypol, the same concentration of Gn is less active in all the cell assays tested. To increase Gn bioavailability, we used PEGylated liposomes in our in vivo studies. Gn-lip via tail vein injection inhibited the growth of human colon cancer DLD-1 xenografts in nude mice, as compared to the untreated control (P
Databáze:	OpenAIRE
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