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A small molecule compound 759 inhibits the wnt/beta-catenin signaling pathway via increasing the Axin protein stability

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Abstract

Wnt/β-catenin signaling plays important role in cancers. Compound 759 is one of the compounds previously screened to identify inhibitors of the Wnt/β-catenin pathway in A549 cells [Lee et al. in Bioorg Med Chem Lett 20:5900–5904, 2010]. However, the mechanism by which Compound 759 induces the inhibition of the Wnt/β-catenin pathway remains unknown. In our study, we employed various assays to comprehensively evaluate the effects of Compound 759 on lung cancer cells. Our results demonstrated that Compound 759 significantly suppressed cell proliferation and Wnt3a-induced Topflash activity and arrested the cell cycle at the G1 stage. Changes in Wnt/β-catenin signaling-related protein expression, gene activity, and protein stability including Axin, and p21, were achieved through western blot and qRT-PCR analysis. Compound 759 treatment upregulated the mRNA level of p21 and increased Axin protein levels without altering the mRNA expression in A549 cells. Co-treatment of Wnt3a and varying doses of Compound 759 dose-dependently increased the amounts of Axin1 in the cytosol and inhibited β-catenin translocation into the nucleus. Moreover, Compound 759 reduced tumor size and weight in the A549 cell-induced tumor growth in the in vivo tumor xenograft mouse model. Our findings indicate that Compound 759 exhibits potential anti-cancer activity by inhibiting the Wnt/β-catenin signaling pathway through the increase of Axin1 protein stability.

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The datasets analyzed and displayed during this research are available from the corresponding authors upon reasonable request.

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Acknowledgements

This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean Government (NRF-2018R1A2B6008860).

Funding

This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean Government (NRF-2018R1A2B6008860).

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Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea

    Seunghan Sun & Yongseok Choi

  2. Innovative Drug-Like Library Research Center, Dongguk University, Seoul, 04625, Republic of Korea

    Young-Dae Gong

  3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, 28116, Republic of Korea

    Jong Soon Kang

  4. College of Pharmacy, Ewha Womans University, Ewhayeodae-gil, Seoul, 03760, Republic of Korea

    Mi-Sook Dong

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Contributions

SS: performed biological experiments and wrote the main manuscript text. JSK prepared Fig. 7. YDG provided Compound 759. MSD provided research funding. MSD and YC are SS advisors and directed the research as co-corresponding authors.

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Correspondence to Mi-Sook Dong.

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Animal experiments were conducted in accordance with the guidelines and approval of the Institutional Animal Care and Use Committee of the Korea Research Institute of Bioscience and Biotechnology (Approval #: KRIBB-AEC-12024).

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Sun, S., Gong, YD., Kang, J.S. et al. A small molecule compound 759 inhibits the wnt/beta-catenin signaling pathway via increasing the Axin protein stability. Med Oncol 41, 147 (2024). https://doi.org/10.1007/s12032-024-02314-8

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