Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death

Marc Schumacher, Claudia Cerella, Serge Eifes, Sébastien Chateauvieux, Franck Morceau, Marcel Jaspars, Mario Dicato, Marc Diederich

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF alpha-treated cells and which genes display an interaction effect between heteronemin and TNF alpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappa B (NF-kappa B) signaling cascade.
We confirmed in silico experiments regarding NF-kappa B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappa B degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC50 of 0.4 mu M. Concomitant to the inhibition of the NF-kappa B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.

Original languageEnglish
Pages (from-to)610-622
Number of pages13
JournalBiochemical Pharmacology
Volume79
Issue number4
Early online date6 Oct 2009
DOIs
Publication statusPublished - 15 Feb 2010

Keywords

  • NF-kappa B
  • marine natural product
  • anti-cancer drug discovery
  • marine natural-products
  • cycle arrest
  • signaling pathways
  • microarray data
  • down-regulation
  • start sites
  • cancer
  • expression
  • biology
  • inflammation

Cite this

Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death. / Schumacher, Marc; Cerella, Claudia; Eifes, Serge; Chateauvieux, Sébastien; Morceau, Franck; Jaspars, Marcel; Dicato, Mario; Diederich, Marc.

In: Biochemical Pharmacology, Vol. 79, No. 4, 15.02.2010, p. 610-622.

Research output: Contribution to journalArticle

Schumacher, Marc ; Cerella, Claudia ; Eifes, Serge ; Chateauvieux, Sébastien ; Morceau, Franck ; Jaspars, Marcel ; Dicato, Mario ; Diederich, Marc. / Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death. In: Biochemical Pharmacology. 2010 ; Vol. 79, No. 4. pp. 610-622.
@article{b30efe25a30341e0bc45270892020a48,
title = "Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death",
abstract = "In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF alpha-treated cells and which genes display an interaction effect between heteronemin and TNF alpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappa B (NF-kappa B) signaling cascade.We confirmed in silico experiments regarding NF-kappa B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappa B degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC50 of 0.4 mu M. Concomitant to the inhibition of the NF-kappa B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.",
keywords = "NF-kappa B, marine natural product, anti-cancer drug discovery, marine natural-products, cycle arrest, signaling pathways, microarray data, down-regulation, start sites, cancer, expression, biology, inflammation",
author = "Marc Schumacher and Claudia Cerella and Serge Eifes and S{\'e}bastien Chateauvieux and Franck Morceau and Marcel Jaspars and Mario Dicato and Marc Diederich",
year = "2010",
month = "2",
day = "15",
doi = "10.1016/j.bcp.2009.09.027",
language = "English",
volume = "79",
pages = "610--622",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through proteasome inhibition and induces apoptotic cell death

AU - Schumacher, Marc

AU - Cerella, Claudia

AU - Eifes, Serge

AU - Chateauvieux, Sébastien

AU - Morceau, Franck

AU - Jaspars, Marcel

AU - Dicato, Mario

AU - Diederich, Marc

PY - 2010/2/15

Y1 - 2010/2/15

N2 - In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF alpha-treated cells and which genes display an interaction effect between heteronemin and TNF alpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappa B (NF-kappa B) signaling cascade.We confirmed in silico experiments regarding NF-kappa B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappa B degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC50 of 0.4 mu M. Concomitant to the inhibition of the NF-kappa B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.

AB - In this study, we investigated the biological effects of heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp. on chronic myelogenous leukemia cells. To gain further insight into the molecular mechanisms triggered by this compound, we initially performed DNA microarray profiling and determined which genes respond to heteronemin stimulation in TNF alpha-treated cells and which genes display an interaction effect between heteronemin and TNF alpha. Within the differentially regulated genes, we found that heteronemin was affecting cellular processes including cell cycle, apoptosis, mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappa B (NF-kappa B) signaling cascade.We confirmed in silico experiments regarding NF-kappa B inhibition by reporter gene analysis, electrophoretic mobility shift analysis and I-kappa B degradation. In order to assess the underlying molecular mechanisms, we determined that heteronemin inhibits both trypsin and chymotrypsin-like proteasome activity at an IC50 of 0.4 mu M. Concomitant to the inhibition of the NF-kappa B pathway, we also observed a reduction in cellular viability. Heteronemin induces apoptosis as shown by annexin V-FITC/propidium iodide-staining, nuclear morphology analysis, pro-caspase-3, -8 and -9 and poly(ADP-ribose) polymerase (PARP) cleavage as well as truncation of Bid. Altogether, results show that this compound has potential as anti-inflammatory and anti-cancer agent.

KW - NF-kappa B

KW - marine natural product

KW - anti-cancer drug discovery

KW - marine natural-products

KW - cycle arrest

KW - signaling pathways

KW - microarray data

KW - down-regulation

KW - start sites

KW - cancer

KW - expression

KW - biology

KW - inflammation

U2 - 10.1016/j.bcp.2009.09.027

DO - 10.1016/j.bcp.2009.09.027

M3 - Article

VL - 79

SP - 610

EP - 622

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 4

ER -