Recent studies have highlighted the importance of the endoplasmic reticulum (ER) in apoptotic processes. In the present study, the traditional herbal medicine ginsenoside Rg3 was used to treat gallbladder cancer in vitro and in vivo. The underlying signaling mechanisms were investigated using various molecular biology techniques, including flow cytometry, western blot analysis, ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was indicated that Rg3 exerted pro-apoptotic activity against the gallbladder cancer cell line GBC-SD through the ER stress-mediated signaling pathway. This was demonstrated by increased expression of phosphorylation of eukaryotic translation-initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein and lipocalin 2. In addition, eIF2α and ATF4 knockdown attenuated the pro-apoptotic effect of Rg3 by inhibiting reactive oxygen species. Furthermore, the results of RT-qPCR analysis indicated that long intergenic non-protein coding RNA-p21 was significantly upregulated following Rg3 treatment. In conclusion, the results of the present study demonstrated that Rg3 inhibited tumor growth in a GBC-SD gallbladder cancer xenograft, by upregulating the ER stress-mediated signaling pathway. Therefore, ER stress activation is suggested to mediate the antitumor effect of Rg3 in gallbladder cancer activity in vitro and in vivo.
Keywords: CCAAT/enhancer-binding protein homologous protein; activating transcription factor 4; endoplasmic reticulum stress; eukaryotic translation-initiation factor 2α; gallbladder cancer; ginsenoside Rg3; glutathione peroxidase; lipocalin 2; long intergenic non-protein coding RNA-p21; reactive oxygen species; superoxide dismutase.