Piperlongumine Inhibits LMP1/MYC-dependent Mouse B-Lymphoma Cells

• Type of Material: Article
• Authors: Dongju Son, Emory University; Seong-Su Han, University of Iowa; Van S. Tompkins, University of Iowa; Natalie L. Kamberos, University of Iowa; Laura L. Stunz, University of Iowa; Ahmad Halwani, University of Iowa; Gail A. Bishop, University of Iowa; Siegfried Janz, University of Iowa
• Language: English
• Date: 2013-07-12
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbrc.2013.06.012
• Title of Journal or Parent Work: Biochemical and Biophysical Research Communications
• Volume: 436
• Issue: 4
• Start Page: 660
• End Page: 665
• Grant/Funding Information: This work was funded by research grants from the NCI (R01CA151354; SJ) and NNSFC (81250110552; VT), as well as additional support by a Hyundai Hope on Wheels Research Scholar Grant (NLK), Roy J. Carver Charitable Trust Collaborative Pilot Grant (GAB and SJ) and the Iowa City Veterans Affairs Medical Center (GAB).
• Keywords: Genes, myc; Viral Matrix Proteins; PL; NF-kappa B; Mice; Cancer therapy and prevention; Animals; p21-Encoding Cdkn1a; BL; Burkitt lymphoma; Lymphoma, B-Cell; Epstein Barr virus; Dioxolanes; Cell Line, Tumor; Transgenic mouse model of human endemic Burkitt lymphoma; Mice, Inbred C57BL; Piperlongumine; NF-κB
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Piperlongumine (PL), isolated from the fruit of Long pepper, Piper longum, is a cancer-inhibiting compound that selectively kills tumor cells while sparing their normal counterparts. Here we evaluated the efficacy with which PL suppresses malignant B cells derived from a newly developed, double-transgenic mouse model of human endemic Burkitt lymphoma (BL), designated mCD40-LMP1/iMycEμ. PL inhibited tumor cell proliferation in a concentration-dependent manner and induced apoptosis of neoplastic but not normal B cells. Treatment with PL resulted in downregulation of EBV-encoded LMP1, cellular Myc, constitutive NF-κB activity, and a host of LMP1-Myc-NF-κB-regulated target genes including Aurka, Bcat1, Bub1b, Ccnb1, Chek1, Fancd2, Tfrc and Xrcc6. Of note, p21Cip1-encoding Cdkn1a was suppressed independent of changes in Trp53 mRNA levels and p53 DNA-binding activity. Considering the central role of the LMP1-NF-κB-Myc axis in B-lineage neoplasia, these findings further our understanding of the mechanisms by which PL inhibits B-lymphoma and provide a preclinical rationale for the inclusion of PL in new interventions in blood cancers.