The Ethyl acetate extract from Celastrus orbiculatus suppresses non-small-cell lung cancer by activating Hippo signaling and inhibiting YAP nuclear translocation

  • Phytomedicine. 2023 Jun:114:154761. doi: 10.1016/j.phymed.2023.154761.
Feng Jin  1 ,  Xiaochen Ni  1 ,  Shilong Yu  2 ,  Xiaomin Jiang  3 ,  Xinlin Shi  1 ,  Jun Zhou  1 ,  Defang Mao  4 ,  Haibo Wang  3 ,  Yanqing Liu  3 ,  Feng Wu  5
Affiliations
  • 1. Department of Respiratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, PR China.
  • 2. Yangzhou Hospital of Traditional Chinese Medicine, Yangzhou, 225001, PR China.
  • 3. The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China; Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China.
  • 4. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China.
  • 5. Department of Respiratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, PR China. Electronic address: [email protected].
PMID: 37028249 DOI: 10.1016/j.phymed.2023.154761
Abstract

Background: Celastrus orbiculatus Thunb. is a medicinal plant that has been widely used for thousands of years in China, and the ethyl acetate extract (Celastrus orbiculatus Thunb. Extract, COE) from its stem was reported to exert antitumor and anti-inflammatory effects in various preclinical studies. However, the anti-non-small-cell lung Cancer activity of COE and its potential mechanism are not yet fully understood.

Purpose: To investigate the antitumor effects of COE on non-small-cell lung Cancer (NSCLC) cells and explore its molecular mechanism from the perspective of Hippo signaling, YAP nuclear translocation, and Reactive Oxygen Species (ROS) generation.

Methods: The effects of COE on proliferation, cell cycle arrest, Apoptosis, stemness, and senescence in NSCLC cell lines were determined by CCK-8, clone formation, flow cytometry, and β-galactosidase staining assays. The effects of COE on Hippo signaling were investigated by Western blotting. The intracellular expression and distribution of YAP were analyzed by immunofluorescence assay. DCFH-DA probe combined with flow cytometry was used to detect intracellular total ROS levels in NSCLC cells after COE treatment. Xenograft tumor model was established, and the animal living image system was employed to analyze the effects of COE on the Hippo-YAP signaling in vivo.

Result: COE significantly inhibited NSCLC activity in vitro and in vivo, mainly by proliferation inhibition, cycle arrest, Apoptosis promotion, senescence promotion, and stemness downregulation. COE strongly activated Hippo signaling and inhibited YAP expression and nuclear retention. Activation of Hippo signaling induced by COE was associated with ROS-mediated phosphorylation of MOB1.

Conclusion: This study demonstrated that COE inhibited NSCLC through activating Hippo signaling and suppressing YAP nuclear translocation, in which ROS may play a role in the phosphorylation of the MOB1 protein.

Keywords
Celastrus orbiculatus extract; Cellular bioenergetics; Hippo signaling; Non-Small-Cell Lung Cancer; YAP.
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