A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened
Copyright © 2024 Elsevier Ltd. All rights reserved..
The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cell chemical biology - (2024) vom: 28. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Yuan-Bin [VerfasserIn] |
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| Links: |
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| Themen: |
Basal cell carcinomas |
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| Anmerkungen: |
Date Revised 05.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.chembiol.2024.02.002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369325427 |
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| 245 | 1 | 2 | |a A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright © 2024 Elsevier Ltd. All rights reserved. | ||
| 520 | |a The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a basal cell carcinomas | |
| 650 | 4 | |a cholesterylation | |
| 650 | 4 | |a cysteine-rich domain | |
| 650 | 4 | |a hedgehog | |
| 650 | 4 | |a medulloblastoma | |
| 650 | 4 | |a smoothened | |
| 650 | 4 | |a vismodegib | |
| 700 | 1 | |a He, Li-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Wen-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Zi-Cun |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Zhi-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yu-Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Ao |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Wen-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Bao-Liang |e verfasserin |4 aut | |
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