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  • Title: HA14-1 sensitizes TNF-alpha-induced apoptosis via inhibition of the NF-kappaB signaling pathway: involvement of reactive oxygen species and JNK.
    Author: Moon DO, Kim MO, Kang SH, Choi YH, Park SY, Kim GY.
    Journal: Cancer Lett; 2010 Jun 01; 292(1):111-8. PubMed ID: 20022690.
    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.
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