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

Abstract EN

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.