Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation
Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation
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DOI：
10.3390/molecules24173110
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发表时间：
2019-08
期刊：
影响因子：
4.6
通讯作者：
Sakiko Nishikawa;Yuka Itoh;Muneshige Tokugawa;Yasumichi Inoue;K. Nakashima;Yuka Hori;Chiharu Miyajima;Kou Yoshida;D. Morishita;Nobumichi Ohoka;M. Inoue;H. Mizukami;T. Makino;H. Hayashi
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作者：
Sakiko Nishikawa;Yuka Itoh;Muneshige Tokugawa;Yasumichi Inoue;K. Nakashima;Yuka Hori;Chiharu Miyajima;Kou Yoshida;D. Morishita;Nobumichi Ohoka;M. Inoue;H. Mizukami;T. Makino;H. Hayashi
在细胞应激反应中，转录激活因子4（ATF 4）调节应激缓解基因和凋亡诱导基因的表达，引发细胞命运决定。由于ATF 4的药理学激活具有强效的抗肿瘤作用，ATF 4激活的调节剂可能在癌症治疗中具有潜力。我们在此试图鉴定激活ATF 4的小分子。使用传统日本汉方医学中使用的生药进行基于细胞的筛选以监测TRB 3启动子活化。我们发现苦参根的提取物表现出有效的TRB 3启动子激活。活性导向分级分离表明，苦参素被确定为活性成分。有趣的是，响应于苦参素的ATF 4活化需要PKR样内质网激酶（PERK）。此外，苦参素诱导细胞周期蛋白依赖性激酶抑制剂p21以及在癌细胞中的细胞停滞。重要的是，通过PERK的药理学抑制降低了苦参素的细胞抑制作用。这些结果表明，苦参素通过PERK触发ATF 4活化，并对癌细胞发挥细胞生长抑制作用。总之，我们的研究结果表明，用苦参素调节PERK-ATF 4通路具有作为癌症治疗的潜力。
In response to cellular stresses, activating transcriptional factor 4 (ATF4) regulates the expression of both stress-relieving genes and apoptosis-inducing genes, eliciting cell fate determination. Since pharmacological activation of ATF4 exerts potent anti-tumor effects, modulators of ATF4 activation may have potential in cancer therapy. We herein attempted to identify small molecules that activate ATF4. A cell-based screening to monitor TRB3 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from Sophora flavescens roots exhibited potent TRB3 promoter activation. The activity-guided fractionation revealed that kurarinone was identified as the active ingredient. Intriguingly, ATF4 activation in response to kurarinone required PKR-like endoplasmic reticulum kinase (PERK). Moreover, kurarinone induced the cyclin-dependent kinase inhibitor p21 as well as cytostasis in cancer cells. Importantly, the cytostatic effect of kurarinone was reduced by pharmacological inhibition of PERK. These results indicate that kurarinone triggers ATF4 activation through PERK and exerts cytostatic effects on cancer cells. Taken together, our results suggest that modulation of the PERK-ATF4 pathway with kurarinone has potential as a cancer treatment.