Cycloprodigiosin hydrocloride suppresses tumor necrosis factor (TNF) alpha-induced transcriptional activation by NF-kappa B

Cycloprodigiosin hydrochloride (cPrG . HCl) obtained from a marine bacteriu m Pseudoalteromonas denitrificans induces apoptotic cell death in various c ancerous cell lines. cPrG . HCl alone caused a little cytotoxicity in HeLa cells, but it enhanced the apoptotic process progressively when co-administ ered with tumor necrosis factor (TNF)alpha. Here we studied the effect of c PrG . HCl on TNF alpha -induced activation of the transcription factor nucl ear factor kappaB (NF-kappaB). Luciferase gene reporter assays revealed tha t cPrG . HCl potently suppressed the TNF alpha- and the phorbol myristate a cetate-induced activation of NF-kappaB. The suppression occurred in the pre sence of imidazole, indicating that it was not related to the intracellular acidification resulting from the intrinsic H+/Cl- symporter activity of cP rG . HCl. cPrG . HCl inhibited neither the TNF alpha -induced phosphorylati on and degradation of inhibitor of nuclear factor-kappaB, nor the subsequen t nuclear translocation and DNA binding of NF-kappaB. cPrG . HCl also suppr essed NF-kappaB-enhanced gene expression induced by Rac1, Cdc42, MEKK1, inh ibitor of nuclear factor-kappa alpha (IKK alpha), IKK beta, and a subunit o f NF-kappaB, p65. These results indicate that cPrG . HCl suppresses NF-kapp aB dependent gene expression through the inhibition of transcriptional acti vation. (C) 2000 Published by Elsevier Science B.V. on behalf of the Federa tion of European Biochemical Societies.