Related Experiment Video
Updated: Jan 20, 2026
Kinases, Phosphatases and Phosphorylation
Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation
Sakiko Nishikawa1, Yuka Itoh1,2, Muneshige Tokugawa1
1Department of Cell Signaling, Graduate School of Pharmaceutical Sciences and Nagoya City University, Nagoya 467-8603, Japan.
Abstract:
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.
Insights
Kurarinone, derived from Sophora flavescens, activates the PERK-ATF4 pathway, inhibiting cancer cell growth. This natural compound shows promise for cancer therapy by modulating stress responses.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- Activating transcriptional factor 4 (ATF4) controls cell fate by regulating stress and apoptosis genes.
- Pharmacological ATF4 activation demonstrates anti-tumor potential, suggesting ATF4 modulators as cancer therapeutics.
Purpose of the Study:
- To identify small molecules that activate ATF4.
- To investigate the anti-cancer properties of compounds derived from traditional Japanese Kampo medicine.
Main Methods:
- A cell-based screening assay monitoring TRB3 promoter activation was employed.
- Activity-guided fractionation of Sophora flavescens root extract identified kurarinone as the active component.
- The role of PKR-like endoplasmic reticulum kinase (PERK) in kurarinone-induced ATF4 activation and cytostasis was assessed.
Main Results:
- Sophora flavescens root extract activated the TRB3 promoter, indicating ATF4 activation.
- Kurarinone was identified as the active ingredient responsible for ATF4 activation.
- Kurarinone-induced ATF4 activation was dependent on PERK and led to p21 induction and cancer cell cytostasis.
- Inhibition of PERK attenuated the cytostatic effects of kurarinone.
Conclusions:
- Kurarinone activates ATF4 through the PERK pathway.
- Kurarinone exhibits cytostatic effects on cancer cells.
- Modulating the PERK-ATF4 pathway with kurarinone represents a potential cancer treatment strategy.
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