Nuclear receptor retinoid-related orphan receptor alpha promotes apoptosis but is reduced in human gastric cancer

Retinoid-related orphan receptor alpha (ROR alpha) is a nuclear receptor, which regulates inflammation and immune responses, lipid metabolism and circadian rhythm. Although ROR alpha suppresses breast tumor invasion, it is unknown whether ROR alpha is dysregulated in gastric cancer leading to cellular survival. Therefore, we hypothesize that ROR alpha is dysfunctional in gastric carcinoma and this causes decreased apoptosis in gastric cancer cells. To test this hypothesis, we employed human gastric cancer tissues with different stages to determine ROR alpha expression, as well as in vitro human gastric cancer cells to determine how ROR alpha is reduced during apoptosis. We found that the expression of ROR alpha was reduced in gastric tissues with cancer, and this correlated with increased TNM stages. The mechanisms underlying ROR alpha reduction is due to the reduced activation of AMP-activated protein kinase (AMPK), as a selective AMPK activator AICAR increased ROR alpha activation and level in human gastric cancer cells. Furthermore, AICAR treatment increased ROR alpha recruitment on the promoters of tumor suppressor genes (i.e., FBXM7, SEMA3F and p21) leading to apoptosis in human gastric cancer cells. Taken together, ROR alpha reduction occurs in gastric cancer leading to the survival of tumor cells, which is attenuated by AMPK. Therefore, both ROR alpha and AMPK are potential targets for the intervention and therapy in gastric carcinoma.