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Molecules 2015, 20(5), 7474-7494; doi:10.3390/molecules20057474

Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines

1
Department of Biology, Boston University, Boston, MA 02215, USA
2
Department of Chemistry, Boston University, Boston, MA 02215, USA
3
Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA
Current address: Department of Cancer Biology, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
*
Author to whom correspondence should be addressed.
Academic Editor: Fernando Albericio
Received: 28 February 2015 / Revised: 12 April 2015 / Accepted: 20 April 2015 / Published: 23 April 2015
(This article belongs to the Section Natural Products)
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Abstract

Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits REL (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells. View Full-Text
Keywords: c-Rel; REL; NF-kappaB; chemical inhibitor; B-cell lymphoma; calafianin; natural product c-Rel; REL; NF-kappaB; chemical inhibitor; B-cell lymphoma; calafianin; natural product
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Yeo, A.T.; Chennamadhavuni, S.; Whitty, A.; Porco, J.A., Jr.; Gilmore, T.D. Inhibition of Oncogenic Transcription Factor REL by the Natural Product Derivative Calafianin Monomer 101 Induces Proliferation Arrest and Apoptosis in Human B-Lymphoma Cell Lines. Molecules 2015, 20, 7474-7494.

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