Kook Sung-Ho, Son Young-Ok, Jang Yong-Suk, Lee Kyung-Yeol, Lee Seung-Ah, Kim Beom-Soo, Lee Hyun-Jeong, Lee Jeong-Chae
Division of Biological Sciences, Chonbuk National University, Chonju 561-756, Korea.
Toxicol Appl Pharmacol. 2008 Mar 15;227(3):468-76. doi: 10.1016/j.taap.2007.11.004. Epub 2007 Nov 17.
Reduction of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun NH2-terminal kinase (JNK) has been implicated in stress-induced apoptosis. However, many studies also emphasize the role of JNK on cell survival, although its mechanisms are not completely understood. Previously, we found that inhibition of JNK activity promotes flavonoid-mediated apoptosis of human osteosarcoma cells. We thus determined whether inhibition of JNK sensitizes tumor cells to a bioflavonoid-induced apoptosis, and whether this effect of JNK is a general effect. As the results, quercetin and genistein as well as a flavonoid fraction induced apoptosis of tumor cells, which was further accelerated by specific JNK inhibitor, SP600125 or by small interfering RNA specific to JNK1/2. This effect was specific to types of cells because it was further apparent in tumorigenic cell lines. Inhibition of JNK by SP600125 also reduced flavonoid-stimulated nuclear induction of JunD which was known to have protective role in apoptosis, whereas JNK inhibition alone had little effect on apoptosis. The flavonoid-induced apoptosis of tumor cells was significantly enhanced by transfecting them with antisense JunD oligonucleotides. These results suggest that inhibition of JNK facilitates flavonoid-induced apoptosis through down-regulation of JunD, which is further sensitive to tumor cells. Therefore, combination with a specific JNK inhibitor further enhances the anti-cancer and chemopreventive potential of bio-flavonoids.
降低对凋亡信号的敏感性是致癌过程中的关键步骤。因此，使肿瘤细胞对凋亡敏感是一种有前景的治疗策略。c-Jun氨基末端激酶（JNK）与应激诱导的凋亡有关。然而，许多研究也强调了JNK在细胞存活中的作用，尽管其机制尚未完全明了。此前，我们发现抑制JNK活性可促进黄酮类化合物介导的人骨肉瘤细胞凋亡。因此，我们确定抑制JNK是否会使肿瘤细胞对生物黄酮诱导的凋亡敏感，以及JNK的这种作用是否具有普遍效应。结果显示，槲皮素、染料木黄酮以及一种黄酮类组分可诱导肿瘤细胞凋亡，特异性JNK抑制剂SP600125或针对JNK1/2的小干扰RNA可进一步加速这种凋亡。这种效应具有细胞类型特异性，因为在致瘤细胞系中更为明显。SP600125抑制JNK也降低了黄酮类化合物刺激的JunD核诱导，已知JunD在凋亡中具有保护作用，而单独抑制JNK对凋亡几乎没有影响。用反义JunD寡核苷酸转染肿瘤细胞可显著增强黄酮类化合物诱导的凋亡。这些结果表明，抑制JNK通过下调JunD促进黄酮类化合物诱导的凋亡，而JunD对肿瘤细胞更为敏感。因此，与特异性JNK抑制剂联合使用可进一步增强生物黄酮的抗癌和化学预防潜力。
