6‑C-(E-Phenylethenyl)Naringenin Attenuates the Stemness of Hepatocellular Carcinoma Cells by Suppressing Wnt/β-Catenin Signaling

• Published in: Journal of agricultural and food chemistry 2019-12, Vol.67 (50), p.13939-13947
• Main Authors: Kang, Qingzheng, Gong, Jun, Wang, Mingfu, Wang, Qiang, Chen, Feng, Cheng, Ka-Wing
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - physiopathology; Cell Proliferation - drug effects; Cell Self Renewal - drug effects; Epithelial-Mesenchymal Transition - drug effects; Female; Flavanones - administration & dosage; Gene Expression Regulation, Neoplastic - drug effects; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - physiopathology; Mice; Mice, Inbred BALB C; Wnt Signaling Pathway - drug effects
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.9b05733

The effect of a novel semi-natural derivative of naringenin, 6-C-(E-phenylethenyl)­naringenin (6-CEPN) on hepatocellular carcinoma (HCC) stemness was evaluated both in vitro and in vivo. 6-CEPN reduced HCC cell viability, inhibited sphere formation, cell migration and invasion, and blocked epithelial–mesenchymal transition. It was equally effective against NANOG+ cells sorted from cultured HCC cells that was accompanied by downregulation of stemness-associated transcription factors and attenuated HIF-1 activity. Furthermore, 6-CEPN significantly enhanced the sensitivity of HCC cells to therapeutic drugs, and inhibited HCC tumor growth and lung metastasis of HCC cells. 6-CEPN suppressed Wnt/β-catenin signaling by inducing β-catenin degradation and inhibiting its nuclear translocation. Upregulation of GSK3β appeared to be crucial for 6-CEPN’s inhibitory activity in the signaling pathway. These findings indicate that 6-CEPN has a strong effect against liver cancer, which is mediated, at least in part, by suppressing the stemness of HCC cells through an action mechanism involving Wnt/β-catenin signaling.