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Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth

Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the...

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Autores principales: Zheng, Shaoqin, Lin, Jiahui, Pang, Zhongqiu, Zhang, Hui, Wang, Yinuo, Ma, Lanjing, Zhang, Haijiao, Zhang, Xi, Chen, Maorong, Zhang, Xinjun, Zhao, Chao, Qi, Jun, Cao, Liu, Wang, Min, He, Xi, Sheng, Ren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534957/
https://www.ncbi.nlm.nih.gov/pubmed/35975457
http://dx.doi.org/10.1002/advs.202200750
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author Zheng, Shaoqin
Lin, Jiahui
Pang, Zhongqiu
Zhang, Hui
Wang, Yinuo
Ma, Lanjing
Zhang, Haijiao
Zhang, Xi
Chen, Maorong
Zhang, Xinjun
Zhao, Chao
Qi, Jun
Cao, Liu
Wang, Min
He, Xi
Sheng, Ren
author_facet Zheng, Shaoqin
Lin, Jiahui
Pang, Zhongqiu
Zhang, Hui
Wang, Yinuo
Ma, Lanjing
Zhang, Haijiao
Zhang, Xi
Chen, Maorong
Zhang, Xinjun
Zhao, Chao
Qi, Jun
Cao, Liu
Wang, Min
He, Xi
Sheng, Ren
author_sort Zheng, Shaoqin
collection PubMed
description Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the elusiveness of the in‐depth mechanism, it is well‐established that pancreatic cancer specially requires abnormal cholesterol metabolism levels for growth. In this study, it is unexpectedly found that among ten Fzds, Fzd5 has a unique capacity to bind cholesterol specifically through its conserved extracellular linker region. Cholesterol‐binding enables Fzd5 palmitoylation, which is indispensable for receptor maturation and trafficking to the plasma membrane. In Wnt‐addicted pancreatic ductal adenocarcinoma (PDAC), cholesterol stimulates tumor growth via Fzd5‐mediated Wnt/β‐catenin signaling. A natural oxysterol, 25‐hydroxylsterol competes with cholesterol and inhibits Fzd5 maturation and Wnt signaling, thereby alleviating PDAC growth. This cholesterol‐receptor interaction and ensuing receptor lipidation uncover a novel mechanism by which Fzd5 acts as a cholesterol sensor and pivotal connection coupling lipid metabolism to morphogen signaling. These findings further suggest that cholesterol‐targeting may provide new therapeutic opportunities for treating Wnt‐dependent cancers.
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spelling pubmed-95349572022-10-11 Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth Zheng, Shaoqin Lin, Jiahui Pang, Zhongqiu Zhang, Hui Wang, Yinuo Ma, Lanjing Zhang, Haijiao Zhang, Xi Chen, Maorong Zhang, Xinjun Zhao, Chao Qi, Jun Cao, Liu Wang, Min He, Xi Sheng, Ren Adv Sci (Weinh) Research Articles Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the elusiveness of the in‐depth mechanism, it is well‐established that pancreatic cancer specially requires abnormal cholesterol metabolism levels for growth. In this study, it is unexpectedly found that among ten Fzds, Fzd5 has a unique capacity to bind cholesterol specifically through its conserved extracellular linker region. Cholesterol‐binding enables Fzd5 palmitoylation, which is indispensable for receptor maturation and trafficking to the plasma membrane. In Wnt‐addicted pancreatic ductal adenocarcinoma (PDAC), cholesterol stimulates tumor growth via Fzd5‐mediated Wnt/β‐catenin signaling. A natural oxysterol, 25‐hydroxylsterol competes with cholesterol and inhibits Fzd5 maturation and Wnt signaling, thereby alleviating PDAC growth. This cholesterol‐receptor interaction and ensuing receptor lipidation uncover a novel mechanism by which Fzd5 acts as a cholesterol sensor and pivotal connection coupling lipid metabolism to morphogen signaling. These findings further suggest that cholesterol‐targeting may provide new therapeutic opportunities for treating Wnt‐dependent cancers. John Wiley and Sons Inc. 2022-08-17 /pmc/articles/PMC9534957/ /pubmed/35975457 http://dx.doi.org/10.1002/advs.202200750 Text en © 2022 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
Zheng, Shaoqin
Lin, Jiahui
Pang, Zhongqiu
Zhang, Hui
Wang, Yinuo
Ma, Lanjing
Zhang, Haijiao
Zhang, Xi
Chen, Maorong
Zhang, Xinjun
Zhao, Chao
Qi, Jun
Cao, Liu
Wang, Min
He, Xi
Sheng, Ren
Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title_full Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title_fullStr Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title_full_unstemmed Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title_short Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth
title_sort aberrant cholesterol metabolism and wnt/β‐catenin signaling coalesce via frizzled5 in supporting cancer growth
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534957/
https://www.ncbi.nlm.nih.gov/pubmed/35975457
http://dx.doi.org/10.1002/advs.202200750
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