Garcimultiflorone K from Garcinia multiflora attenuates hepatocellular carcinoma metastasis by suppressing transforming growth factor-β signaling.

Affiliation

Huang SF(1), Wang YL(2), Chen JJ(3), Huang YB(4), Tai SB(5), Chung CL(2), Chen CL(6).
Author information:
(1)Department of Medicine Chest, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan ROC.
(2)Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan ROC.
(3)Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming Chiao-Tung University, Taipei 11221, Taiwan ROC; Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan ROC.
(4)Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC.
(5)Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan ROC; Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 81342, Taiwan ROC.
(6)Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan ROC; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC; Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan ROC. Electronic address: [Email]

Abstract

BACKGROUND: Transforming growth factor‑β (TGF-β) signaling is a crucial inducer of tissue fibrosis and extracellular matrix accumulation and a vital suppressor of epithelial cell proliferation and cancer metastasis. The nature of this multifunctional cytokine has prompted the development of TGF-β signaling inhibitors as therapeutic agents. Our research group has recently isolated the polyprenylated polycyclic acylphloroglucinol garcimultiflorone K (GMK) from the stems of Garcinia multiflora; GMK exhibits antiangiogenic activity in endothelial cells. PURPOSE: In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Garcimultiflorone K in hepatocellular carcinoma cells. METHODS: Cell proliferation and viability were evaluated using the MTT assay. The migratory ability of HepG2 cells was measured using wound healing assays. The inhibitory effect of GMK against the nuclear translocation of Smad by TGF-β was assessed through immunofluorescence staining and Western blotting. To investigate TGF-β-dependent gene expression profiles upon GMK stimulation, RNA transcript levels were determined using reverse transcription polymerase chain reaction. The effects of GMK in Smad2-driven transcriptomic activities were studied using a reporter gene assay. Protein levels were detected using Western blotting. RESULTS: Our data revealed that GMK inhibited TGF-β-induced cellular responses, including Smad protein phosphorylation, cell migration, and extracellular matrix production, during epithelial-mesenchymal transition (EMT). Mechanistic studies further demonstrated that GMK suppressed TGF-β signaling by downregulating TGF-β receptor II (TβRII). CONCLUSION: These findings elucidate that TβRII expression in hepatic cells can be specifically suppressed by GMK to attenuate metastasis and the disease-promoting effects of EMT, representing a therapeutic approach.