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

Suk FM, Lien GS, Huang WJ, Chen CN, Lu SY, Yang YC, Yan MD, Liang YC - Evid Based Complement Alternat Med (2013)

Bottom Line: First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.

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 2 α (eIF2 α ), 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.

No MeSH data available.


Related in: MedlinePlus

Structure of NBM-TP-007-GS-002 (GS-002).
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fig1: Structure of NBM-TP-007-GS-002 (GS-002).

Mentions: Besides traditional synthetic compounds, many natural products were found to exert anticancer effects. Identification of the active components and their mechanisms of action are important to assess their potential for clinical use and possible diverse side effects. Propolis, a natural resinous product, is collected from various plant sources by honeybees, which use it to seal holes in their honeycombs. Propolis was reported to exhibit a broad spectrum of activities including antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, hepatoprotective, and anticancer properties [24, 25]. Ten propolins (propolins A~J) of the active components were isolated and characterized. Our previous studies suggested that propolin G (PPG) isolated from Taiwanese green propolis induced growth inhibition and apoptosis of brain cancer cells possibly due to modulating expressions of cell cycle-regulator genes and further activating caspase cascades and mitochondrial pathways, ultimately resulting in the induction of apoptosis [26]. We were interested in developing more-potent antitumor activity from PPG and found that the PPG derivative, NBM-TP-007-GS-002 (GS-002) (Figure 1), was a more-potent antitumor drug than was the parental PPG. In this study, we further investigated the molecular mechanism of GS-002 in inhibiting hepatoma cell proliferation.


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

Suk FM, Lien GS, Huang WJ, Chen CN, Lu SY, Yang YC, Yan MD, Liang YC - Evid Based Complement Alternat Med (2013)

Structure of NBM-TP-007-GS-002 (GS-002).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814109&req=5

fig1: Structure of NBM-TP-007-GS-002 (GS-002).
Mentions: Besides traditional synthetic compounds, many natural products were found to exert anticancer effects. Identification of the active components and their mechanisms of action are important to assess their potential for clinical use and possible diverse side effects. Propolis, a natural resinous product, is collected from various plant sources by honeybees, which use it to seal holes in their honeycombs. Propolis was reported to exhibit a broad spectrum of activities including antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, hepatoprotective, and anticancer properties [24, 25]. Ten propolins (propolins A~J) of the active components were isolated and characterized. Our previous studies suggested that propolin G (PPG) isolated from Taiwanese green propolis induced growth inhibition and apoptosis of brain cancer cells possibly due to modulating expressions of cell cycle-regulator genes and further activating caspase cascades and mitochondrial pathways, ultimately resulting in the induction of apoptosis [26]. We were interested in developing more-potent antitumor activity from PPG and found that the PPG derivative, NBM-TP-007-GS-002 (GS-002) (Figure 1), was a more-potent antitumor drug than was the parental PPG. In this study, we further investigated the molecular mechanism of GS-002 in inhibiting hepatoma cell proliferation.

Bottom Line: First, we found that GS-002 significantly inhibited cell proliferation and induced cell apoptosis in dose-dependent manners.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.

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 2 α (eIF2 α ), 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.

No MeSH data available.


Related in: MedlinePlus