HA14-1 sensitizes TNF-alpha-induced apoptosis via inhibition of the NF-kappa B signaling pathway: Involvement of reactive oxygen species and JNK

作者：Moon Dong Oh; Kim Mun Ock; Kang Sang Hyuck; Choi Yung Hyun; Park Sung Yong; Kim Gi Young^*

来源：Cancer Letters, 2010, 292(1): 111-118.

DOI：10.1016/j.canlet.2009.11.014

• HA14-1
• TNF-alpha
• NF-kappa B
• ROS
• JNK

Nuclear factor-kappa B (NF-kappa B) activation by tumor necrosis factor-alpha (TNF-alpha) attenuates the TNF-alpha-induced apoptosis pathway. Thus, blockage of NF-kappa B 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-kappa B, reactive oxygen species (ROS), and c-Jun N-terminal kinase (INK) 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-kappa B activation. HA14-1 suppressed NF-kappa B activation through inhibition of phosphorylation and degradation of I kappa B alpha. This inhibition was correlated with suppression of NF-kappa B-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 TNT-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.

• 出版日期2010-6-1