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.

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.

• Authors: Alan T Yeo, Spandan Chennamadhavuni, Adrian Whitty, John A Porco Jr, Thomas D Gilmore
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 5 Pg. 7474-94 (Apr 23 2015) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 25915462 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BCL2L1 protein, human
• DNA-Binding Proteins
• Lipopolysaccharides
• NF-kappa B p50 Subunit
• Proto-Oncogene Proteins c-rel
• RELA protein, human
• Transcription Factor RelA
• bcl-X Protein
• calafianin
• Tyrosine

Topics

• 3T3 Cells
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (antagonists & inhibitors)
• Enzyme Activation (drug effects)
• HEK293 Cells
• Humans
• L Cells
• Lipopolysaccharides
• Lymphoma, B-Cell (drug therapy)
• Macrophages (metabolism)
• Mice
• NF-kappa B p50 Subunit (antagonists & inhibitors)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-rel (antagonists & inhibitors)
• Transcription Factor RelA (antagonists & inhibitors)
• Tyrosine (analogs & derivatives, pharmacology)
• bcl-X Protein (biosynthesis)