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Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway

Acta Pharmacologica Sinica volume 46, pages 2016–2028 (2025)Cite this article

Abstract

Gene therapy, epigenetic therapies, natural compounds targeted therapy, photodynamic therapy, nanoparticles, and precision medicines are becoming available to diagnose and treat cancer. Gracillin, a natural steroidal saponin extracted from herbs, has shown potent efficacy against a range of malignancies. In this study, we investigated the molecular anticancer mechanisms of gracillin. We showed that gracillin dose-dependently suppressed proliferation, migration, and invasion in breast cancer, liver cancer, and glioblastoma cells with IC50 values around 1 μM, which were associated with MST-independent activation of Hippo signaling pathway and subsequent decreased YAP activity. We demonstrated that gracillin activated the Hippo signaling by inducing Merlin/LATS protein-protein interaction (PPI). A competitive inhibitory peptide (SP) derived from the binding interface of the PPI, disrupted the interaction, abolishing the anticancer activity of gracillin. In nude mice bearing MDA-MB-231, HCCLM3, or U87MG xenograft tumor, administration of gracillin (5, 10 mg·kg−1·d−1, i.g. for 21 days) dose-dependently suppressed the tumor growth, associated with the induced Merlin/LATS PPI, activated Hippo signaling, as well as decreased YAP activity in tumor tissues. Our data demonstrate that gracillin is an efficacious therapeutic agent for cancer treatment, induction of Merlin/LATS PPI might provide proof-of-concept in developing therapeutic agent for cancer treatment.

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Fig. 1
Fig. 2: Gracillin suppresses proliferation, migration, and invasion in cancer cells.
Fig. 3: Gracillin activates Hippo signaling pathway in cancer cells.
Fig. 4: Gracillin exhibits anticancer effects dependent on YAP activity.
Fig. 5: Gracillin induces Merlin/LATS protein-protein interaction in cancer cells.
Fig. 6: Gracillin suppresses cell proliferation, migration, and invasion via Merlin/LATS PPI-induced activation of Hippo signaling pathway.
Fig. 7: Gracillin activates Hippo signaling and suppresses tumor growth in vivo.
Fig. 8: Schematic illustration of gracillin-induced suppression of cancer through Merlin/LATS interaction associated activation of the Hippo signaling pathway.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81973341), the Guangdong Basic and Applied Basic Research Foundation (2024A1515013108), and the Medical Joint Fund of Jinan University (YXJC2022002).

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China

    Jin-xuan Su, Hai-xia Zhou, Zhi-jing Zhang, Xiao-feng Zhou, Qiu-ming Zou, Si-jia Li, Xiao-song Zhuang, Si-yu Yang, Kai Cui, Yong-qi Liu, Rui-jie Yuan, Zi-sheng Li, Han-yun Tu, Mei Cheng, Qi Qi & Yu-bo Zhang

  2. Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China

    Zhi-jing Zhang

  3. Department of Colorectal & Anal Surgery, Guangzhou First People’s Hospital, Guangzhou, 510632, China

    Jian-qin Lai

  4. Department of Respiratory and Critical Care, The First Hospital of China Medical University, Shenyang, 110001, China

    Yong-qi Liu

  5. Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia

    Heng-xin Pan

  6. Functional Experimental Teaching Center, School of Medicine, Jinan University, Guangzhou, 510632, China

    Yu Yan

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  1. Jin-xuan Su
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  2. Hai-xia Zhou
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Contributions

JXS designed the protocols, performed experiments, drew the figures, and wrote the manuscript. HXZ, ZJZ, and XFZ performed experiments. QMZ, SJL, JQL, SYY, YQL, and RJY contributed to the data collection. XSZ, KC, and HXP provided technical support. ZSL, and HYT contributed to data analysis. MC, YY, QQ, and YBZ funding acquisition, project administration, supervision, revise the manuscript.

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Correspondence to Mei Cheng, Yu Yan, Qi Qi or Yu-bo Zhang.

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Su, Jx., Zhou, Hx., Zhang, Zj. et al. Gracillin suppresses cancer progression through inducing Merlin/LATS protein-protein interaction and activating Hippo signaling pathway. Acta Pharmacol Sin 46, 2016–2028 (2025). https://doi.org/10.1038/s41401-025-01514-w

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