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

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 IC(50) 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.