Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation
by
Sakiko Nishikawa 1,†, Yuka Itoh 1,2,†, Muneshige Tokugawa 1, Yasumichi Inoue 1,3,*
, Ken-ichi Nakashima 4, Yuka Hori 1, Chiharu Miyajima 1,3, Kou Yoshida 1, Daisuke Morishita 1, Nobumichi Ohoka 5, Makoto Inoue 4, Hajime Mizukami 6,‡, Toshiaki Makino 6 and Hidetoshi Hayashi 1,3,*
Sakiko Nishikawa 1,†, Yuka Itoh 1,2,†, Muneshige Tokugawa 1, Yasumichi Inoue 1,3,*, Ken-ichi Nakashima 4, Yuka Hori 1, Chiharu Miyajima 1,3, Kou Yoshida 1, Daisuke Morishita 1, Nobumichi Ohoka 5, Makoto Inoue 4, Hajime Mizukami 6,‡, Toshiaki Makino 6 and Hidetoshi Hayashi 1,3,*
1
Department of Cell Signaling, Graduate School of Pharmaceutical Sciences and Nagoya City University, Nagoya 467-8603, Japan
2
Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan
3
Department of Innovative Therapeutic Sciences, Cooperative Major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
4
Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, Nagoya 464-8650, Japan
5
Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 210-9501, Japan
6
Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Present address: The Kochi Prefectural Makino Botanical Garden, Kochi 781-8125, Japan.
Academic Editor: Tran Dang Xuan
Molecules 2019, 24(17), 3110; https://doi.org/10.3390/molecules24173110
Received: 8 August 2019 / Revised: 23 August 2019 / Accepted: 23 August 2019 / Published: 27 August 2019
(This article belongs to the Special Issue Discovery of Active Ingredients from Natural Products)
Simple Summary
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.
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Keywords:
ATF4; cancer; ISR; kurarinone; PERK; Sophora flavescens; TRB3
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MDPI and ACS Style
Nishikawa, S.; Itoh, Y.; Tokugawa, M.; Inoue, Y.; Nakashima, K.-I.; Hori, Y.; Miyajima, C.; Yoshida, K.; Morishita, D.; Ohoka, N.; Inoue, M.; Mizukami, H.; Makino, T.; Hayashi, H. Kurarinone from Sophora Flavescens Roots Triggers ATF4 Activation and Cytostatic Effects Through PERK Phosphorylation. Molecules 2019, 24, 3110.
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