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Mar. Drugs 2018, 16(12), 489;

Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-β Pathway

Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA
Department of Pediatrics, E-DA Hospital, Kaohsiung 824, Taiwan
School of Medicine, I-Shou University, Kaohsiung 824, Taiwan
School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
Graduate Institute of Nanomedicine and Medical Engineering, College of Medical Engineering, Taipei Medical University, Taipei 11031, Taiwan
The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Joint Biobank, Office of Human Research, Taipei Medical University, Taipei 11031, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 3 November 2018 / Revised: 26 November 2018 / Accepted: 30 November 2018 / Published: 6 December 2018
PDF [3015 KB, uploaded 14 December 2018]


A marine sesterterpenoid-type natural product, heteronemin, retains anticancer effects. In the current study, we investigate the antitumor mechanism of heteronemin in cholangiocarcinoma cells and further explore its molecular targets. Initially, heteronemin exhibited potent cytotoxic effects against cholangiocarcinoma HuccT1 and SSP-25 cells. In vitro, heteronemin altered the abilities of cell adhesion and cell migration in HuccT1 and SSP-25 cell lines. It repressed messenger ribonucleic acid (mRNA) expression levels of transforming growth factor (TGF)-β, mothers against decapentaplegic homolog (SMAD) and Myc, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. In addition, heteronemin altered several signaling pathways. The results indicate that heteronemin was able to modulate cell adhesion, the expression of extracellular matrix (ECM) receptors, the TGF-β pathway, cell motility, the membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, the regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in cholangiocarcinoma cell lines. The results also suggest that it activated multiple signal transduction pathways to induce an anti-proliferation effect and anti-metastasis in cholangiocarcinoma. In conclusion, heteronemin may be used as a potential medicine for anticancer therapy. View Full-Text
Keywords: heteronemin; cholangiocarcinoma; TGF-β pathway heteronemin; cholangiocarcinoma; TGF-β pathway

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Lin, H.-Y.; Tey, S.-L.; Ho, Y.; Chin, Y.-T.; Wang, K.; Whang-Peng, J.; Shih, Y.-J.; Chen, Y.-R.; Yang, Y.-N.; Chen, Y.-C.; Liu, Y.-C.; Tang, H.-Y.; Yang, Y.-C.S. Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-β Pathway. Mar. Drugs 2018, 16, 489.

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