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Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 658370, 11 pages
http://dx.doi.org/10.1155/2013/658370
Research Article

A Taiwanese Propolis Derivative Induces Apoptosis through Inducing Endoplasmic Reticular Stress and Activating Transcription Factor-3 in Human Hepatoma Cells

1Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
2Graduate Institute of Pharmacognosy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3New Drug Research and Development Center, NatureWise Biotech & Medicals Corporation, Nankang, Taipei 115, Taiwan
4School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan
5Department of Animal Science, College of Bioresources, National Ilan University, Ilan 260, Taiwan
6Center of Excellence for Cancer Research, Taipei Medical University, Taipei 110, Taiwan
7Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan

Received 18 May 2013; Accepted 1 September 2013

Academic Editor: Andreas Sandner-Kiesling

Copyright © 2013 Fat-Moon Suk et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Activating transcription factor-(ATF-) 3, a stress-inducible transcription factor, is rapidly upregulated under various stress conditions and plays an important role in inducing cancer cell apoptosis. NBM-TP-007-GS-002 (GS-002) is a Taiwanese propolin G (PPG) derivative. In this study, we examined the antitumor effects of GS-002 in human hepatoma Hep3B and HepG2 cells in vitro. First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners. Several main apoptotic indicators were found in GS-002-treated cells, such as the cleaved forms of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). GS-002 also induced endoplasmic reticular (ER) stress as evidenced by increases in ER stress-responsive proteins including glucose-regulated protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153), phosphorylated eukaryotic initiation factor 2α (eIF2α), phosphorylated protein endoplasmic-reticular-resident kinase (PERK), and ATF-3. The induction of ATF-3 expression was mediated by mitogen-activated protein kinase (MAPK) signaling pathways in GS-002-treated cells. Furthermore, we found that GS-002 induced more cell apoptosis in ATF-3-overexpressing cells. These results suggest that the induction of apoptosis by the propolis derivative, GS-002, is partially mediated through ER stress and ATF-3-dependent pathways, and GS-002 has the potential for development as an antitumor drug.