The synthetic epoxyquinoids jesterone dimer and epoxyquinone A monomer induce apoptosis and inhibit REL (human c-Rel) DNA binding in an IkappaBalpha-deficient diffuse large B-cell lymphoma cell line.
The NF-kappaB transcription factor signaling pathway is constitutively active in many human cancers, and inhibition of this pathway can often kill cancer cells by inducing apoptosis. In this study, we show that two synthetic epoxyquinoids, jesterone dimer (JD) and epoxyquinone A monomer (EqM), are equally effective at inhibiting the growth of two human lymphoma cell lines that have constitutively nuclear REL (human c-Rel) DNA-binding complexes, but either express (SUDHL-4 cells) or do not express (RC-K8 cells) the NF-kappaB inhibitor IkappaBalpha. Furthermore, in these cells, both JD and EqM dose-dependently induced apoptosis, inhibited REL DNA-binding activity, and converted REL to a high molecular weight form. In A293 cells, JD and EqM inhibited the DNA-binding activity of overexpressed REL, but not p50. Replacement of Cys-27 with Ser in REL reduced JD- and EqM-mediated inhibition of REL DNA-binding activity. These results suggest that JD and EqM can induce apoptosis in IkappaBalpha-deficient lymphoma cells through a mechanism involving direct inhibition of transcription factor REL.
Liang
Mei-Chih
MC
Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
Bardhan
Sujata
S
Porco
John A
JA
Gilmore
Thomas D
TD
D000475:Alkenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004852:Epoxy Compounds / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha; D011809:Quinones / Q000494:pharmacology*
D000475:Alkenes; D017931:DNA Primers; D004273:DNA, Neoplasm; D004852:Epoxy Compounds; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D011809:Quinones; C508869:epoxyquinone A; C431025:jesterone; D000072000:NF-KappaB Inhibitor alpha