Involvement of nuclear receptor RZR/ROR gamma in melatonin-induced HIF-1 alpha inactivation in SGC-7901 human gastric cancer cells

摘要

The melatonin nuclear receptor is an orphan member of the nuclear receptor superfamily RZR/ROR, which consists of three subtypes (alpha, beta and gamma), suggesting that immunomodulatory and antitumor effects through the intracellular action of melatonin depend on nuclear signaling. In the present study, the biological mechanisms of melatonin were elucidated in association with the RZR/RORy pathway in SGC-7901 human gastric cancer cells under hypoxia. Melatonin suppressed the activity of RZR/ROR gamma and SUMO-specific protease 1 (SENP1) signaling pathway, which is essential for stabilization of hypoxia-inducible factor-1 alpha (HIF-1 alpha) during hypoxia. Furthermore, melatonin inhibited the stability of HIF-1 alpha in a time- and concentration-dependent manner in SGC-7901 human gastric cancer cells during hypoxia. Consistently, siRNA-RZR/ROR gamma effectively blocked the expression of SENP1, HIF-1 alpha and vascular endothelial growth factor (VEGF) production in SGC-7901 cells under hypoxia, suggesting the role of nuclear receptor RZR/ROR gamma in melatonin-inhibited HIF-1 alpha and VEGF accumulation. Moreover, siRNA RZR/RORy obviously antagonized to inhibit the action of the gastric cancer cell proliferation by melatonin. Our findings suggest that melatonin suppresses HIF-1 alpha accumulation and VEGF generation via inhibition of melatonin nuclear receptor RZR/ROR gamma in SGC-7901 cells under hypoxia.