NGF Inhibits Human Leukemia Proliferation by Downregulating Cyclin A1 Expression through Promoting Acinus/CtBP2 Association

• Type of Material: Article
• Authors: Chi Bun Chan, Emory University; Xia Liu, Emory University; Sung-Wuk Jang, Emory University; Stephen I-Hong Hsu, National University of Singapore; Ifor Williams, Emory University; Sumin Kang, Emory University; Jing Chen, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2009-10-29
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Macmillan Publishers Limited. All Rights Reserved.
• Final Published Version (URL): http://www.nature.com/onc/journal/v28/n43/full/onc2009236a.html
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 28
• Issue: 43
• Start Page: 3825
• End Page: 3836
• Grant/Funding Information: This work is supported by Grant from NIH (RO1 NS060680) to K.Ye. We would like to thank Dr. G. Chinnadurai (Saint Louis University Health Sciences Center) for GST-CtBP1 plasmid.
• Keywords: Gambogic amide; CtBP2; NGF; Leukemia; Acinus; Cyclin A1
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by acinus, a nuclear speckle protein. However, the molecular mechanism of how acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds acinus, which is regulated by NGF, inhibiting its stimulatory effect on cyclin A1 but not cyclin A2 expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and acinus through triggering acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF’s suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF down-regulates cyclin A1 expression through escalating CtBP2/acinus complex formation, and gambogic amide might be useful for human leukemia treatment.