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

in Acta pharmacologica Sinica by Jin-Xuan Su, Hai-Xia Zhou, Zhi-Jing Zhang, Xiao-Feng Zhou, Qiu-Ming Zou, Si-Jia Li, Xiao-Song Zhuang, Jian-Qin Lai, Si-Yu Yang, Kai Cui, Yong-Qi Liu, Rui-Jie Yuan, Heng-Xin Pan, Zi-Sheng Li, Han-Yun Tu, Mei Cheng, Yu Yan, Qi Qi, Yu-Bo Zhang

TLDR

  • Gracillin, a natural steroidal saponin, inhibits cancer cell proliferation, migration, and invasion by activating the Hippo signaling pathway and suppresses tumor growth in nude mice.
  • The study demonstrates the potential of gracillin as a therapeutic agent for cancer treatment and provides a proof-of-concept for developing Merlin/LATS PPI-based therapies.

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 ICvalues 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·d, 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.

Overview

  • The study investigated the molecular anticancer mechanisms of gracillin, a natural steroidal saponin extracted from herbs, and its efficacy against breast cancer, liver cancer, and glioblastoma.
  • The researchers demonstrated that gracillin dose-dependently suppressed proliferation, migration, and invasion in cancer cells, with IC values around 1 μM, and showed its ability to induce Hippo signaling pathway activation and decreased YAP activity.
  • The study aimed to understand the molecular mechanisms of gracillin's anticancer effects, with potential applications in developing therapeutic agents for cancer treatment.

Comparative Analysis & Findings

  • Gracillin demonstrated potent efficacy against a range of malignancies, including breast cancer, liver cancer, and glioblastoma, with IC values around 1 μM.
  • The study showed that gracillin dose-dependently suppressed tumor growth in nude mice bearing MDA-MB-231, HCCLM3, or U87MG xenograft tumor, associated with the induction of Merlin/LATS PPI and activated Hippo signaling.
  • A competitive inhibitory peptide (SP) derived from the binding interface of the Merlin/LATS PPI disrupted the interaction, abolishing the anticancer activity of gracillin.

Implications and Future Directions

  • The study demonstrates that gracillin is an efficacious therapeutic agent for cancer treatment, and induction of Merlin/LATS PPI might provide proof-of-concept in developing therapeutic agents for cancer treatment.
  • Future studies could aim to explore the potential mechanisms of gracillin's resistance to cancer cells and identify targets for combination therapies.
  • The development of novel therapeutic strategies using gracillin or its analogues could improve cancer treatment outcomes.
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