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