Toxicology & Applied Pharmacology, 2012, 262(3):247-54.

Genistein enhances the effect of trichostatin A on inhibition of A549 cell growth by increasing expression of TNF receptor-1

Tzu-Chin Wu, Ying-Chihi Yang, Pei-Ru Huang, et al

Chest Clinic, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC; et al

Our previous study has shown that genistein enhances apoptosis in A549 lung cancer cells induced by trichostatin A (TSA). The precise molecular mechanism underlying the effect of genistein, however, remains unclear. In the present study, we investigated whether genistein enhances the anti-cancer effect of TSA through up-regulation of TNF receptor-1 (TNFR-1) death receptor signaling. We incubated A549 cells with TSA (50 ng/mL) alone or in combination with genistein and then determined the mRNA and protein expression of TNFR-1 as well as the activation of downstream caspases. Genistein at 5 and 10 μM significantly enhanced the TSA-induced decrease in cell number and apoptosis in a dose-dependent manner. The combined treatment significantly increased mRNA and protein expression of TNFR-1 at 6 and 12 h, respectively, compared with that of the control group; while TSA alone had no effect. TSA in combination with 10 μM of genistein increased TNFR-1 mRNA and protein expression by about 70% and 40%, respectively. The underlying mechanism for this effect of genistein may be partly associated with the estrogen receptor pathway. The combined treatment also increased the activation of caspase-3 and ‐10 as well as p53 protein expression in A549 cells. The enhancing effects of genistein on the TSA-induced decrease in cell number and on the expression of caspase-3 in A549 cells were suppressed by silencing TNFR-1 expression. These data demonstrated that the upregulation of TNFR-1 death receptor signaling plays an important role, at least in part, in the enhancing effect of genistein on TSA-induced apoptosis in A549 cells.

美国《毒理学与应用药理学》，2012年8月

染料木黄酮通过增强TNF受体-1 的表达增强曲古菌素对A549 细胞生长的抑制作用

吴世金， 杨英晖，黄佩茹等

中国台湾中山医药大学附属医院胸部门诊科等

我们先前的研究表明，染料木黄酮可以促进曲 古霉素(TSA) 诱导 的A549 肺癌细胞凋亡。然而，金雀异黄素作用的准确分子机制仍不清楚。在本研究中，我们研究了染料木黄酮是否通过上调肿瘤坏死因子受体-1 (TNFR-1) 死亡受体信号增强了TSA的抗肿瘤效应。我们单独用TSA (50 ng/mL) 或者联合金雀异黄素共同培育A549 细胞，然后测定 TNFR-1的 mRNA 及蛋白表达以及下游半胱氨酸蛋白酶的活性。5 和 10 μM的染料木黄酮以依赖剂量的方式明显增强了 TSA 诱导的细胞数量减少和细胞凋亡。联合的治疗方法分别在 6 和 12 h明显提高了 TNFR-1的 mRNA 和蛋白表达，与对照组相比；虽然单独使用TSA的效果不明显。与10 μM 金雀异黄素联合使用的TSA分别提升 TNFR-1的 mRNA 及蛋白表达约 70%和 40%。金雀异黄素这种效应的基本机理可能与雌激素受体途径部分关联。联合治疗也增加了A549 细胞中半胱氨酸蛋白酶-3 和 ‐10 激活以及p53 蛋白的表达。在 A549 细胞中染料木黄酮对 TSA 诱导的细胞数量减少和半胱氨酸蛋白酶-3表达下调的增强效应被静默TNFR-1 的表达抑制。这些数据表明，上调 TNFR-1 死亡受体信号转导，至少部分地，在金雀异黄素增强TSA 诱导的A549细胞凋亡等方面发挥重要作用。