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.
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.
Department of Biology, Boston University, Boston, MA 02215, USA. alanyeo@bu.edu.
Alan T
AT
Yeo
Department of Chemistry, Boston University, Boston, MA 02215, USA. schennam@gmail.com.|Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA. schennam@gmail.com.
Spandan
S
Chennamadhavuni
Department of Chemistry, Boston University, Boston, MA 02215, USA. whitty@bu.edu.|Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA. whitty@bu.edu.
Adrian
A
Whitty
Department of Chemistry, Boston University, Boston, MA 02215, USA. porco@bu.edu.|Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA. porco@bu.edu.
John A
JA
Porco
Department of Biology, Boston University, Boston, MA 02215, USA. gilmore@bu.edu.|Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA 02215, USA. gilmore@bu.edu.
Thomas D
TD
Gilmore
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007739:L Cells; D008070:Lipopolysaccharides; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051020:bcl-X Protein / Q000096:biosynthesis
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051020:bcl-X Protein; C412924:calafianin; D014443:Tyrosine