Berghe Wim Vanden, De Naeyer An, Dijsselbloem Nathalie, David Jean-Pierre, De Keukeleire Denis, Haegeman Guy
Ghent University (UGent), Department of Physiology, Laboratory of Eukaryotic Gene Expression and Signal Transduction, Ledeganckstraat, Ghent, Belgium.
Endocr Metab Immune Disord Drug Targets. 2011 Sep 1;11(3):247-61. doi: 10.2174/187153011796429790.
We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, metastasis, and subversion of immunity, and changes responsivity to hormones and to chemotherapeutics. Our results in estrogen-unresponsive fibroblasts, ribosomal S6 kinase 2 kinase (RSK2) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that kurarinone can inhibit tumor cell proliferation and selectively block nuclear NFκB transactivation of specific target genes such as IL6, cyclin D1, SOD2 but not TNFAIP2. This occurs via attenuation of extracellular signal-regulated protein (ERK) and RSK2 kinase pathways and inhibition of S6 kinase ribosomal protein (S6RP) and histone H3 S10 phosphorylation. As constitutive NFκB and RSK2 activity are important hallmarks of human cancers, including hematopoietic malignancies and solid tumors, prenylated flavanones represent an attractive class of natural inhibitors of the ERK/RSK2 signaling pathway for cancer therapy.
我们已经从分子层面详细分析了苦参中分离出的薰衣草基黄酮苦参酮如何抑制核因子-κB（NFκB）驱动的白细胞介素-6（IL6）表达和癌细胞生长。白细胞介素-6（IL6）参与癌症相关炎症，作为一种自分泌和旁分泌生长因子，促进血管生成、转移和免疫颠覆，并改变对激素和化疗药物的反应性。我们在雌激素无反应性成纤维细胞、核糖体S6激酶2激酶（RSK2）基因敲除细胞和雌激素受体（ER）缺陷型乳腺肿瘤细胞中的研究结果表明，苦参酮可以抑制肿瘤细胞增殖，并选择性地阻断特定靶基因如IL6、细胞周期蛋白D1、超氧化物歧化酶2（SOD2）而非肿瘤坏死因子α诱导蛋白2（TNFAIP2）的核NFκB反式激活。这是通过减弱细胞外信号调节蛋白（ERK）和RSK2激酶途径以及抑制S6激酶核糖体蛋白（S6RP）和组蛋白H3 S10磷酸化来实现的。由于组成型NFκB和RSK2活性是人类癌症（包括血液系统恶性肿瘤和实体瘤）的重要标志，异戊烯化黄酮类化合物是一类有吸引力的ERK/RSK2信号通路天然抑制剂，可用于癌症治疗。
