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Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1–10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.

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Fig. 1: Sequence analysis and structure of human FZDs and the binding pattern of haXWnt8–mFzd8CRD–hLRP6E1E2 (PDB code 8CTG).
Fig. 2: Canonical Wnt/FZD signal transduction.
Fig. 3: Non-canonical WNT pathways.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Grant number 82172686), and Beijing Natural Science Foundation (Grant numbers 7202088, 7212152).

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  1. These authors contributed equally: Hui-yu Liu, Xiao-jiao Sun

Authors and Affiliations

  1. Department of Otorhinolaryngology Head and Neck Surgery, Peking University First Hospital, Beijing, 100034, China

    Hui-yu Liu, Jun-yan Liu, Yu-song Dai & Tian-cheng Li

  2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China

    Xiao-jiao Sun, Si-yu Xiu, Xiang-yu Zhang, Zhi-qi Wang, Chu-xiao Yi, Xia Yuan & Zhen-ming Liu

  3. Department of Pharmacy, Peking University First Hospital, Beijing, 100034, China

    Yan-lun Gu & Xiao-cong Pang

  4. Yizhang County People’s Hospital, Chenzhou, 424200, China

    Hua-peng Liao

  5. Department of Otorhinolaryngology Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100034, China

    Tian-cheng Li

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Liu, Hy., Sun, Xj., Xiu, Sy. et al. Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01270-3

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