Department of Cell Signaling, Graduate School of Pharmaceutical Sciences and Nagoya City University, Nagoya 467-8603, Japan.
Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Molecules. 2019 Aug 27;24(17):3110. doi: 10.3390/molecules24173110.
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 promoter activation was performed using crude drugs used in traditional Japanese Kampo medicine. We found that an extract from roots exhibited potent 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.
细胞应激时，激活转录因子 4（ATF4）调节压力缓解基因和凋亡诱导基因的表达，引发细胞命运决定。由于 ATF4 的药理学激活具有强大的抗肿瘤作用，因此 ATF4 激活调节剂可能在癌症治疗中有应用潜力。我们在此尝试鉴定激活 ATF4 的小分子。使用传统日本汉方药中的粗提物进行基于细胞的筛选，以监测启动子激活。我们发现一种来自根的提取物具有很强的启动子激活作用。活性导向的分离揭示了苦参酮被鉴定为有效成分。有趣的是，苦参酮对 ATF4 的激活需要 PKR 样内质网激酶（PERK）。此外，苦参酮诱导细胞周期蛋白依赖性激酶抑制剂 p21 以及癌细胞的细胞停滞。重要的是，PERK 的药理学抑制降低了苦参酮的细胞停滞作用。这些结果表明，苦参酮通过 PERK 触发 ATF4 激活，并对癌细胞发挥细胞停滞作用。总之，我们的结果表明，用苦参酮调节 PERK-ATF4 通路可能作为癌症治疗的一种方法。
