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异常胆固醇代谢与 Wnt/β-连环蛋白信号通过卷曲蛋白 5 协同作用以支持肿瘤生长。

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

机构信息

College of Life and Health Science, Northeastern University, Shenyang, 110819, P. R. China.

College of Sciences, Northeastern University, Shenyang, 110004, P. R. China.

出版信息

Adv Sci (Weinh). 2022 Oct;9(28):e2200750. doi: 10.1002/advs.202200750. Epub 2022 Aug 17.

DOI:10.1002/advs.202200750
PMID:35975457
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9534957/
Abstract

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.

摘要

卷曲蛋白（Fzd）是 Wnt 受体，在发育、内稳态和肿瘤发生中发挥重要作用。Wnt/Fzd 信号如何与生理调节偶联仍然未知。胆固醇被报道为一种信号分子，可调节形态发生素如 Hedgehog 信号。尽管深入的机制尚不清楚，但已经确立的是，胰腺癌特别需要异常的胆固醇代谢水平来生长。在这项研究中，令人意外地发现，在十个 Fzds 中，Fzd5 具有通过其保守的细胞外连接区特异性结合胆固醇的独特能力。胆固醇结合使 Fzd5 棕榈酰化，这对于受体成熟和向质膜的运输是必不可少的。在依赖 Wnt 的胰腺导管腺癌 (PDAC) 中，胆固醇通过 Fzd5 介导的 Wnt/β-catenin 信号刺激肿瘤生长。一种天然的氧化固醇，25-羟固醇与胆固醇竞争，并抑制 Fzd5 成熟和 Wnt 信号，从而减轻 PDAC 的生长。这种胆固醇-受体相互作用和随之而来的受体脂质化揭示了 Fzd5 作为胆固醇传感器和连接脂质代谢和形态发生素信号的关键连接的新机制。这些发现进一步表明，胆固醇靶向可能为治疗依赖 Wnt 的癌症提供新的治疗机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/f0406b45ea34/ADVS-9-2200750-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/009973e71ecf/ADVS-9-2200750-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/c6d5747aa031/ADVS-9-2200750-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/f045a023b894/ADVS-9-2200750-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/f0406b45ea34/ADVS-9-2200750-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/009973e71ecf/ADVS-9-2200750-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/864289e532a5/ADVS-9-2200750-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/aec05d150895/ADVS-9-2200750-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/b204c6fba8b3/ADVS-9-2200750-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/c6d5747aa031/ADVS-9-2200750-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/f045a023b894/ADVS-9-2200750-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b1a6/9534957/f0406b45ea34/ADVS-9-2200750-g004.jpg

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