Cycloprodigiosin hydrocloride suppresses tumor necrosis factor (TNF) α-induced transcriptional activation by NF-κB

Cycloprodigiosin hydrochloride (cPrG . HCl) obtained from a marine bacterium Pseudoalteromonas denitrificans induces apoptotic cell death in various cancerous cell lines. cPrG . HCl alone caused a little cytotoxicity in HeLa cells, but it enhanced the apoptotic process progressively when co-administered with tumor necrosis factor (TNF)alpha. Here we studied the effect of cPrG . HCl on TNF alpha -induced activation of the transcription factor nuclear factor kappaB (NF-kappaB). Luciferase gene reporter assays revealed that cPrG . HCl potently suppressed the TNF alpha- and the phorbol myristate acetate-induced activation of NF-kappaB. The suppression occurred in the presence of imidazole, indicating that it was not related to the intracellular acidification resulting from the intrinsic H+/Cl- symporter activity of cPrG . HCl. cPrG . HCl inhibited neither the TNF alpha -induced phosphorylation and degradation of inhibitor of nuclear factor-kappaB, nor the subsequent nuclear translocation and DNA binding of NF-kappaB. cPrG . HCl also suppressed NF-kappaB-enhanced gene expression induced by Rac1, Cdc42, MEKK1, inhibitor of nuclear factor-kappa alpha (IKK alpha), IKK beta, and a subunit of NF-kappaB, p65. These results indicate that cPrG . HCl suppresses NF-kappaB dependent gene expression through the inhibition of transcriptional activation. (C) 2000 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.