Periplocin and cardiac glycosides suppress the unfolded protein response
| Autor: | Chiharu Miyajima, Daisuke Morishita, Yasumichi Inoue, Masaki Ri, Hajime Mizukami, Kan'ichiro Ishiuchi, Shinsuke Iida, Muneshige Tokugawa, Nobumichi Ohoka, Michiyo Matsuno, Hidetoshi Hayashi, Yuka Itoh, Toshiaki Makino, Chisane Kujirai |
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| Rok vydání: | 2021 |
| Předmět: |
X-Box Binding Protein 1
endocrine system Cell signaling XBP1 RNA Splicing Science Activating transcription factor Endoplasmic Reticulum digestive system Article Cell Line Cardiac Glycosides Small Molecule Libraries Cell Line Tumor Translational regulation Humans Protein kinase A Periploca Multidisciplinary Molecular medicine Plant Extracts Chemistry ATF6 Endoplasmic reticulum fungi Saponins Cell biology HEK293 Cells biological sciences Unfolded Protein Response Unfolded protein response Medicine Signal Transduction Cell signalling |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | The unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR. Here, we screened small-molecule compounds that suppress UPR, using a library of Myanmar wild plant extracts. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. We isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure–activity relationship of periplocin revealed that cardiac glycosides also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to our understanding of the pathological or physiological importance of UPR. |
| Databáze: | OpenAIRE |
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