HA14-1 sensitizes TNF-alpha-induced apoptosis via inhibition of the NF-kappaB signaling pathway: involvement of reactive oxygen species and JNK.

Abstract

Nuclear factor-kappa B (NF-kappaB) activation by tumor necrosis factor-alpha (TNF-alpha) attenuates the TNF-alpha-induced apoptosis pathway. Thus, blockage of NF-kappaB activity may improve the anti-cancer activity of TNF-alpha. HA14-1 induces apoptosis in various human cancer cells, and the molecular mechanisms of this action remain to be fully characterized. The present study evaluated the involvement of NF-kappaB, reactive oxygen species (ROS), and c-Jun N-terminal kinase (JNK) in the effects of HA14-1 by examining the sensitization effect on TNF-alpha-induced apoptosis in human leukemia cells. Such sensitization is closely associated with the inhibitory effect of HA14-1 on TNF-alpha-mediated NF-kappaB activation. HA14-1 suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha. This inhibition was correlated with suppression of NF-kappaB-dependent gene products (c-myc, cyclin D1, cox-2, and IAP-1). Additionally, the present findings provide evidence of a critical role of ROS accumulation induced by HA14-1 in TNF-alpha-induced apoptosis. Moreover, HA14-1 also markedly sustained TNF-alpha-mediated JNK activation. A specific JNK inhibitor abolished the sensitization effect of HA14-1 on TNF-alpha-induced apoptosis. Taken together, these results indicate that ROS and JNK represent important signals in HA14-1 sensitization in TNF-alpha-induced apoptosis.

• Authors: Dong-Oh Moon, Mun-Ock Kim, Sang-Hyuck Kang, Yung Hyun Choi, Sung Yong Park, Gi-Young Kim
• Journal: Cancer letters (Cancer Lett) Vol. 292 Issue 1 Pg. 111-8 (Jun 01 2010) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 20022690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzopyrans
• DNA, Neoplasm
• NF-kappa B
• Nitriles
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
• MAP Kinase Kinase 4

Topics

• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Cell Line, Tumor
• DNA, Neoplasm (metabolism)
• Enzyme Activation
• Humans
• Leukemia (metabolism, pathology)
• MAP Kinase Kinase 4 (metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Nitriles (pharmacology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)