Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors
Abstract Epidermal growth factor receptor (EGFR) inhibitors frequently cause severe skin rash as a side effect, which is a critical burden for patients who continuously receive drug treatments. Several recent clinical trials have shown that vitamin K is effective against these side effects; however,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-49627-8 |
| _version_ | 1797388354340257792 |
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| author | Shotaro Goto Shuichi Setoguchi Daisuke Watase Hirofumi Yamakawa Ayano Yamada Mitsuhisa Koga Koichi Matsuo Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata |
| author_facet | Shotaro Goto Shuichi Setoguchi Daisuke Watase Hirofumi Yamakawa Ayano Yamada Mitsuhisa Koga Koichi Matsuo Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata |
| author_sort | Shotaro Goto |
| collection | DOAJ |
| description | Abstract Epidermal growth factor receptor (EGFR) inhibitors frequently cause severe skin rash as a side effect, which is a critical burden for patients who continuously receive drug treatments. Several recent clinical trials have shown that vitamin K is effective against these side effects; however, the underlying mechanisms remain unclear. EGFR inhibitors induce C–C motif chemokine ligand 5 (CCL5) in dermopathy. We hypothesized that menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)), supplied by biosynthesis or external delivery, is essential for the suppressive effect on CCL5. The aim of this study was to explore the underlying mechanisms governing the relieving effects of MKH against skin rashes caused by EGFR inhibitors. The responses generated by EGFR inhibitors and the effect of MKH derivatives (two ester derivatives and MK-4) on them were evaluated using human skin cell lines (HaCaT and HSC-1). EGFR inhibitors downregulated UbiA prenyltransferase domain-containing protein-1 (UBIAD1, MKH synthetase) expression and MKH biosynthesis. Knockdown of UBIAD1 or γ-glutamyl carboxylase and treatment with warfarin upregulated CCL5 expression. MKH derivatives suppressed the CCL5 expression induced by EGFR inhibitors. Our data strongly suggest that MKH is involved in suppressing CCL5 expression and alleviating the skin damage caused by EGFR inhibitors. |
| first_indexed | 2024-03-08T22:39:32Z |
| format | Article |
| id | doaj.art-8e5a8ad35f7e4f73afa7a366fb7ff542 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T22:39:32Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8e5a8ad35f7e4f73afa7a366fb7ff5422023-12-17T12:16:23ZengNature PortfolioScientific Reports2045-23222023-12-011311910.1038/s41598-023-49627-8Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitorsShotaro Goto0Shuichi Setoguchi1Daisuke Watase2Hirofumi Yamakawa3Ayano Yamada4Mitsuhisa Koga5Koichi Matsuo6Kazuhisa Matsunaga7Yoshiharu Karube8Jiro Takata9Faculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityRadioisotope Center, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityFaculty of Pharmaceutical Sciences, Fukuoka UniversityAbstract Epidermal growth factor receptor (EGFR) inhibitors frequently cause severe skin rash as a side effect, which is a critical burden for patients who continuously receive drug treatments. Several recent clinical trials have shown that vitamin K is effective against these side effects; however, the underlying mechanisms remain unclear. EGFR inhibitors induce C–C motif chemokine ligand 5 (CCL5) in dermopathy. We hypothesized that menahydroquinone-4 (MKH), the active form of menaquinone-4 (MK-4, vitamin K2(20)), supplied by biosynthesis or external delivery, is essential for the suppressive effect on CCL5. The aim of this study was to explore the underlying mechanisms governing the relieving effects of MKH against skin rashes caused by EGFR inhibitors. The responses generated by EGFR inhibitors and the effect of MKH derivatives (two ester derivatives and MK-4) on them were evaluated using human skin cell lines (HaCaT and HSC-1). EGFR inhibitors downregulated UbiA prenyltransferase domain-containing protein-1 (UBIAD1, MKH synthetase) expression and MKH biosynthesis. Knockdown of UBIAD1 or γ-glutamyl carboxylase and treatment with warfarin upregulated CCL5 expression. MKH derivatives suppressed the CCL5 expression induced by EGFR inhibitors. Our data strongly suggest that MKH is involved in suppressing CCL5 expression and alleviating the skin damage caused by EGFR inhibitors.https://doi.org/10.1038/s41598-023-49627-8 |
| spellingShingle | Shotaro Goto Shuichi Setoguchi Daisuke Watase Hirofumi Yamakawa Ayano Yamada Mitsuhisa Koga Koichi Matsuo Kazuhisa Matsunaga Yoshiharu Karube Jiro Takata Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors Scientific Reports |
| title | Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors |
| title_full | Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors |
| title_fullStr | Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors |
| title_full_unstemmed | Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors |
| title_short | Menahydroquinone-4 may play a key role in regulating CCL5 expression induced by epidermal growth factor receptor inhibitors |
| title_sort | menahydroquinone 4 may play a key role in regulating ccl5 expression induced by epidermal growth factor receptor inhibitors |
| url | https://doi.org/10.1038/s41598-023-49627-8 |
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