Evodiamine inhibits proliferation and promotes apoptosis of hepatocellular carcinoma cells via the Hippo-Yes-Associated Protein signaling pathway

• Published in: Life sciences (1973) Vol. 251; pp. 117424 - 14
• Main Authors: Zhao, Shuang, Xu, Ke, Jiang, Rong, Li, Dan-Yang, Guo, Xing-Xian, Zhou, Peng, Tang, Jia-Feng, Li, Li-Sha, Zeng, Di, Hu, Ling, Ran, Jian-Hua, Li, Jing, Chen, Di-Long
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.06.2020; Elsevier BV
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Anti-cancer effects; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Bioinformatics; Biotechnology; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Evodiamine; Female; Flow cytometry; Hep G2 Cells; Hepatocellular carcinoma; Hippo-YAP signaling pathway; Humans; Immunoblotting; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Plants; Polymerase chain reaction; Protein-Serine-Threonine Kinases - metabolism; Proteins; Quinazolines - pharmacology; Signal transduction; Signal Transduction - drug effects; Signaling; Transcription Factors; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Yes-associated protein; Hepatocellular carcinoma; Hippo-YAP signaling pathway; Evodiamine; Anti-cancer effects
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.117424

Dysfunction of the Hippo-Yes-Associated Protein (YAP) signaling pathway is known to be associated with hepatocellular carcinoma (HCC). Evodiamine (Evo), a plant-derived bioactive alkaloid, exerts inhibitory effects on cancer. However, the precise influence of Evo on HCC and its potential effects on Hippo-YAP signaling have yet to be ascertained. Here, the effects of Evo on cell proliferation and apoptosis were evaluated using HCC cell lines (HepG2 and Bel-7402) and nude mice with xenograft tumors. We further investigated whether Evo exerts anti-HCC activity through effects on Hippo-YAP signaling in vitro with the aid of XMU-MP-1, an inhibitor of the key component of this pathway, mammalian sterile 20-like kinase 1/2. Cell proliferation and apoptosis were assessed using 5-ethynyl-2′-deoxyuridine staining, colony formation, flow cytometry, hematoxylin-eosin and dUTP nick-end labeling experiments. Bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR) arrays were performed to determine the associations among Evo, HCC progression and the Hippo-YAP pathway. The expression patterns of components of Hippo-YAP signaling and apoptotic genes were further examined via RT-qPCR and immunoblotting. Evo inhibited proliferation and promoted apoptosis of HCC cell lines in vitro, and attenuated xenograft tumor formation in nude mice in vivo. Mechanistically, Evo treatment stimulated the Hippo-YAP signaling pathway. In vitro, the effects of Evo on HCC cell proliferation and apoptosis were alleviated by XMU-MP-1. Our collective results revealed that the anti-HCC effects of Evo were correlated with the Hippo-YAP signaling pathway. Evodiamine (Evo) is derived from the Chinese herbal medicine Evodia rutaecarpa Bentham. Data from the present study confirmed that Evo exerted an inhibitory effect on proliferation and promotes apoptosis of HepG2 and Bel-7402 cells in vitro. Xenograft tumor formation studies revealed that Evo impairs in vivo tumor growth. Mechanistic studies further indicated that the phenotypes caused by Evo are attributed to activation of mammalian sterile 20-like kinase 1/2 (Mst1/2) and upregulation of large tumor suppressor 1 (Lats1) phosphorylation, leading to phosphorylation and decreased nuclear translocation of Yes-Associated Protein (YAP) protein and consequent deactivation of its downstream effectors. Abbreviations: transcriptional coactivator with PDZ-binding motif (TAZ), TEA domain transcription factor (TEAD), connective tissue growth factor (CTGF), B-cell lymphoma/leukemia (Bcl-2), Bcl-2-associated X protein (Bax). [Display omitted]