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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Neveskin from Ferula samarcandica exerts anti-gastric cancer effects via the Hippo-YAP signaling pathway
Mayire Nueraihemaiti1, Khamidulla Kamoldinov2, Xueying Lu3
1State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China; China College of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing 100039, China.
Background:
Gastric cancer remains a major global health burden, accounting for substantial morbidity and mortality worldwide. The development of effective therapeutic agents, particularly those capable of selectively targeting tumor cells while minimizing cytotoxicity in normal tissues, represents an urgent unmet clinical need. Neveskin, a sesquiterpene coumarin derived from the Central Asian medicinal plant Ferula samarcandica, has recently emerged as a promising candidate due to its potent antitumor activities and favorable pharmacological profile.
Purpose:
To examine Neveskin's antitumor effects against gastric cancer via Hippo-YAP pathway-mediated autophagy and apoptosis.
Methods:
The antitumor activity of Neveskin was evaluated both in vitro and in vivo. For in vitro studies, gastric cancer cell lines HGC-27 and SGC-7901 were used. Cell proliferation, migration, and invasion were assessed by MTT assay, colony formation assay, wound healing assay, and Transwell assay, respectively. Apoptosis and cell cycle distribution were analyzed by flow cytometry. The expression of epithelial-mesenchymal transition (EMT), autophagy, and apoptosis-related markers was detected by Western blotting. The role of YAP was verified via siRNA-mediated knockdown. The binding mode and affinity of Neveskin to key target proteins were investigated using integrated molecular docking, molecular dynamics simulations, and the Cellular Thermal Shift Assay (CETSA). For in vivo evaluation, the HGC-27 xenograft model was established in BALB/c nude mice. The therapeutic efficacy of Neveskin was examined, and tumor tissues were analyzed by TUNEL assay, immunohistochemistry (IHC), and hematoxylin and eosin (H&E) staining.
Results:
Neveskin dose-dependently suppressed proliferation, migration, and invasion in HGC-27 and SGC-7901 gastric cancer cells, concurrent with EMT marker downregulation and apoptosis induction. Neveskin triggered G0/G1 cell cycle arrest and enhanced autophagic flux. siRNA-mediated YAP ablation confirmed Hippo-YAP pathway dependency for these antitumor activities. CETSA experiments demonstrated high-affinity binding of Neveskin to LATS1. In vivo, Neveskin significantly suppressed tumor growth and Ki-67 proliferation index while enhancing apoptosis in xenograft models.
Conclusion:
This study is the first to demonstrate that Neveskin exhibits potent anti-gastric cancer effects by dually modulating the Hippo-YAP-mediated autophagy and apoptosis pathways. These findings establish a robust preclinical foundation for developing Neveskin as a promising therapeutic candidate against gastric malignancies.
