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Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating throu...

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Autores principales: Zhao, Xinyuan, Guo, Bing, Sun, Wenjuan, Yu, Jinhua, Cui, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520660/
https://www.ncbi.nlm.nih.gov/pubmed/37490552
http://dx.doi.org/10.1002/advs.202206878
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author Zhao, Xinyuan
Guo, Bing
Sun, Wenjuan
Yu, Jinhua
Cui, Li
author_facet Zhao, Xinyuan
Guo, Bing
Sun, Wenjuan
Yu, Jinhua
Cui, Li
author_sort Zhao, Xinyuan
collection PubMed
description Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating through a cholesterol‐dependent pathway. Comprehensive transcriptomic analysis reveals that SQLE is essential for maintaining c‐Myc transcriptional activity by stabilizing the c‐Myc protein and averting its ubiquitin‐mediated degradation. Mechanistic investigation demonstrates that SQLE inhibition diminishes Akt's binding affinity to lipid rafts via a cholesterol‐dependent process, subsequently deactivating lipid raft‐localized Akt, reducing GSK‐3β phosphorylation at S9, and increasing c‐Myc phosphorylation at T58, ultimately leading to c‐Myc destabilization. Importantly, employing an Sqle conditional knockout mouse model, SQLE's critical role in HNSCC initiation and progression is established. The preclinical findings demonstrate the potent synergistic effects of combining terbinafine and cisplatin in arresting tumor growth. These discoveries not only provide novel insights into the underlying mechanisms of SQLE‐mediated cisplatin resistance and tumorigenesis in HNSCC but also propose a promising therapeutic avenue for HNSCC patients unresponsive to conventional cisplatin‐based chemotherapy.
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spelling pubmed-105206602023-09-27 Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC Zhao, Xinyuan Guo, Bing Sun, Wenjuan Yu, Jinhua Cui, Li Adv Sci (Weinh) Research Articles Cisplatin resistance poses a substantial hurdle in effectively treating head and neck squamous cell carcinoma (HNSCC). Utilizing multiple tumor models and examining an internal HNSCC cohort, squalene epoxidase (SQLE) is pinpointed as a key driver of chemoresistance and tumorigenesis, operating through a cholesterol‐dependent pathway. Comprehensive transcriptomic analysis reveals that SQLE is essential for maintaining c‐Myc transcriptional activity by stabilizing the c‐Myc protein and averting its ubiquitin‐mediated degradation. Mechanistic investigation demonstrates that SQLE inhibition diminishes Akt's binding affinity to lipid rafts via a cholesterol‐dependent process, subsequently deactivating lipid raft‐localized Akt, reducing GSK‐3β phosphorylation at S9, and increasing c‐Myc phosphorylation at T58, ultimately leading to c‐Myc destabilization. Importantly, employing an Sqle conditional knockout mouse model, SQLE's critical role in HNSCC initiation and progression is established. The preclinical findings demonstrate the potent synergistic effects of combining terbinafine and cisplatin in arresting tumor growth. These discoveries not only provide novel insights into the underlying mechanisms of SQLE‐mediated cisplatin resistance and tumorigenesis in HNSCC but also propose a promising therapeutic avenue for HNSCC patients unresponsive to conventional cisplatin‐based chemotherapy. John Wiley and Sons Inc. 2023-07-25 /pmc/articles/PMC10520660/ /pubmed/37490552 http://dx.doi.org/10.1002/advs.202206878 Text en © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhao, Xinyuan
Guo, Bing
Sun, Wenjuan
Yu, Jinhua
Cui, Li
Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title_full Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title_fullStr Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title_full_unstemmed Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title_short Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC
title_sort targeting squalene epoxidase confers metabolic vulnerability and overcomes chemoresistance in hnscc
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10520660/
https://www.ncbi.nlm.nih.gov/pubmed/37490552
http://dx.doi.org/10.1002/advs.202206878
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