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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

The propolis derivative, GS-002, induced endoplasmic reticular stress in human hepatoma cells. Hep3B cells were treated (a) with 20 μg/mL GS-002 for the indicated time periods or (b) with various concentrations of GS-002 for 12 h. Total cell lysates were used to detect protein expressions of GRP78, GADD153, phospho-eIF2α (p-eIF2α), phosphor-PERK (p-PEK), and α-tubulin by Western blotting.
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fig4: The propolis derivative, GS-002, induced endoplasmic reticular stress in human hepatoma cells. Hep3B cells were treated (a) with 20 μg/mL GS-002 for the indicated time periods or (b) with various concentrations of GS-002 for 12 h. Total cell lysates were used to detect protein expressions of GRP78, GADD153, phospho-eIF2α (p-eIF2α), phosphor-PERK (p-PEK), and α-tubulin by Western blotting.

Mentions: It was suggested that prolonged ER stress can cause cells to undergo apoptosis. To examine whether GS-002 also caused apoptosis through ER stress in human hepatoma cells, several ER-responsive proteins and ER-specific signals were detected. We first measured expressions of GRP78, which acts as a gatekeeper in activating ER stress, and GADD153, a transcription factor increased by ER stress. The Western blot analysis showed that expressions of GRP78 and GADD153 significantly increased after GS-002 treatment in dose- and time-dependent manners (Figure 4). We next detected the phosphorylation of ER-specific signals, including PERK and eIF2α, which are known to be activated in response to accumulation of unfolded proteins in the ER lumen. As shown in Figure 4, GS-002 indeed induced the phosphorylation of PERK and its substrate, eIF2α, in dose- and time-dependent manners. The results suggested that GS-002 was able to induce ER stress in Hep3B cells.


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)

The propolis derivative, GS-002, induced endoplasmic reticular stress in human hepatoma cells. Hep3B cells were treated (a) with 20 μg/mL GS-002 for the indicated time periods or (b) with various concentrations of GS-002 for 12 h. Total cell lysates were used to detect protein expressions of GRP78, GADD153, phospho-eIF2α (p-eIF2α), phosphor-PERK (p-PEK), and α-tubulin by Western blotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: The propolis derivative, GS-002, induced endoplasmic reticular stress in human hepatoma cells. Hep3B cells were treated (a) with 20 μg/mL GS-002 for the indicated time periods or (b) with various concentrations of GS-002 for 12 h. Total cell lysates were used to detect protein expressions of GRP78, GADD153, phospho-eIF2α (p-eIF2α), phosphor-PERK (p-PEK), and α-tubulin by Western blotting.
Mentions: It was suggested that prolonged ER stress can cause cells to undergo apoptosis. To examine whether GS-002 also caused apoptosis through ER stress in human hepatoma cells, several ER-responsive proteins and ER-specific signals were detected. We first measured expressions of GRP78, which acts as a gatekeeper in activating ER stress, and GADD153, a transcription factor increased by ER stress. The Western blot analysis showed that expressions of GRP78 and GADD153 significantly increased after GS-002 treatment in dose- and time-dependent manners (Figure 4). We next detected the phosphorylation of ER-specific signals, including PERK and eIF2α, which are known to be activated in response to accumulation of unfolded proteins in the ER lumen. As shown in Figure 4, GS-002 indeed induced the phosphorylation of PERK and its substrate, eIF2α, in dose- and time-dependent manners. The results suggested that GS-002 was able to induce ER stress in Hep3B cells.

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