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

Abstract

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)α. Here we studied the effect of cPrG·HCl on TNFα-induced activation of the transcription factor nuclear factor κB (NF-κB). Luciferase gene reporter assays revealed that cPrG·HCl potently suppressed the TNFα- and the phorbol myristate acetate-induced activation of NF-κB. 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 TNFα-induced phosphorylation and degradation of inhibitor of nuclear factor-κB, nor the subsequent nuclear translocation and DNA binding of NF-κB. cPrG·HCl also suppressed NF-κB-enhanced gene expression induced by Rac1, Cdc42, MEKK1, inhibitor of nuclear factor-κα (IKKα), IKKβ, and a subunit of NF-κB, p65. These results indicate that cPrG·HCl suppresses NF-κB-dependent gene expression through the inhibition of transcriptional activation.