Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju, Republic of Korea.
Cancer Lett. 2010 Jun 1;292(1):111-8. doi: 10.1016/j.canlet.2009.11.014. Epub 2009 Dec 22.
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.
核因子-κB（NF-κB）的激活肿瘤坏死因子-α（TNF-α）减弱 TNF-α 诱导的凋亡途径。因此，NF-κB 活性的阻断可能提高 TNF-α 的抗癌活性。HA14-1 在各种人类癌细胞中诱导凋亡，而这种作用的分子机制仍有待充分阐明。本研究通过检测 HA14-1 对人白血病细胞中 TNF-α 诱导的凋亡的增敏作用，评估了 NF-κB、活性氧（ROS）和 c-Jun N-末端激酶（JNK）的参与。这种增敏作用与 HA14-1 对 TNF-α 介导的 NF-κB 激活的抑制作用密切相关。HA14-1 通过抑制 IkappaBalpha 的磷酸化和降解来抑制 NF-κB 的激活。这种抑制与 NF-κB 依赖性基因产物（c-myc、cyclin D1、cox-2 和 IAP-1）的抑制相关。此外，本研究结果提供了证据表明 ROS 的积累由 HA14-1 诱导在 TNF-α 诱导的凋亡中起着关键作用。此外，HA14-1 还明显维持 TNF-α 介导的 JNK 激活。一种特异性的 JNK 抑制剂消除了 HA14-1 对 TNF-α 诱导的凋亡的增敏作用。总之，这些结果表明 ROS 和 JNK 代表了 HA14-1 在 TNF-α 诱导的凋亡中的增敏作用中的重要信号。
