Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth.
Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth.
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异常胆固醇代谢和 Wnt/β-Catenin 信号通过 Frizzled5 结合以支持癌症生长
DOI：
10.1002/advs.202200750
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发表时间：
2022-10
期刊：
影响因子：
15.1
通讯作者：
Sheng, Ren
中科院分区：
文献类型：
--
作者：
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
卷曲蛋白(FZD)是Wnt受体，在发育、动态平衡和肿瘤发生中发挥重要作用。Wnt/Fzd信号是如何与生理调节相结合的，目前尚不清楚。据报道，胆固醇是一种信号分子，调节形态原，如Hedgehog信号。尽管深入的机制尚不清楚，但众所周知，胰腺癌的生长特别需要异常的胆固醇代谢水平。在这项研究中，人们意外地发现，在十个FZD中，FZD5具有通过其保守的胞外连接区与胆固醇特异结合的独特能力。胆固醇结合使Fzd5棕榈酰化，这是受体成熟和转运到质膜所必需的。在Wnt成瘾的胰腺导管腺癌中，胆固醇通过FZD5介导的Wnt/β-catenin信号刺激肿瘤生长。一种天然的氧甾醇，25-羟基甾醇与胆固醇竞争，抑制Fzd5成熟和Wnt信号，从而减缓PDAC的生长。这种胆固醇-受体的相互作用和随后的受体脂化揭示了Fzd5作为胆固醇传感器的新机制，以及连接脂质代谢和形态原信号的关键连接。这些发现进一步表明，胆固醇靶向可能为治疗Wnt依赖的癌症提供新的治疗机会。胰腺癌中FrizzledFZD受体调节和胆固醇代谢异常的机制在很大程度上还不清楚。这项研究表明，胆固醇与FZD5特异性结合，使FZD5成熟，激活胰腺癌所需的Wnt/β-catenin信号。因此，Fzd5关键地结合了胆固醇代谢和Wnt/β-连环蛋白信号，而氧固醇在癌症治疗中提供了新的治疗前景。
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. The mechanism of Frizzled (Fzd) receptor regulation and aberrant cholesterol metabolism in pancreatic cancer are largely unknown. This study reveals that cholesterol specifically binds to Fzd5 and enables Fzd5 maturation to activate Wnt/β‐catenin signaling which is required for pancreatic cancer. Therefore, Fzd5 crucially coalesces cholesterol metabolism and Wnt/β‐catenin signaling, and oxysterol provides new therapeutic promise in cancer treatment.
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