Suppression of estrogen receptor-beta promotes gastric cancer cell apoptosis with induction of autophagy

Estrogen Receptor 2 (ESR2) is the protein-coding gene of estrogen receptor beta (ER beta) and has been shown to be abundantly expressed in gastric carcinoma (GC), suggesting that it plays a role in GC pathogenesis. However, the underlying molecular mechanism remains elusive. In the present in vitro study, GC cell growth was found to be estrogen-dependent, and the expression level of ER beta was higher than that of ER alpha. Knocking down the endogenous expression of ESR2 in GC cells increased the apoptosis rate and the level of cleaved caspase-3, caspase-7 and poly ADP-ribose polymerase. The induced apoptosis was primarily related to GC cell growth arrest, accompanied with activation of DNA damage-inducible protein 45 alpha (GADD45 alpha) in a p53-independent manner. Importantly, down-regulation of ESR2 also promoted autophagy. The autophagy inhibitor 3-MA or silencing ATG7 rescued the apoptosis by knocking down ESR2 via activation of the MAPK signaling pathway in AGS cells, leading to increased apoptosis. In conclusion, these results demonstrated that suppression of ESR2 gene expression could promote GC cell apoptosis, suggesting that it may prove to be a potential therapeutic target for GC.