Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo.

Abstract

An adequate supply of oxygen and nutrients, derived from the formation of novel blood vessels, is critical for the growth and expansion of tumor cells. It has been demonstrated that melatonin (MLT) exhibits marked in vitro and in vivo oncostatic activities. The primary purpose of the present study was to evaluate the in vitro and in vivo antitumor activity of MLT on the growth and angiogenesis of gastric cancer cells, and explore the underlying molecular mechanisms. The present results revealed that MLT inhibited the growth of gastric cancer SGC-7901 cells in a dose- and time-dependent manner. In addition, the present study demonstrated that low concentrations (0.01, 0.1 and 1 mM) of MLT had no clear effect on vascular endothelial growth factor (VEGF) secretion, whereas a high concentration (3 mM) of MLT suppressed VEGF secretion in SGC-7901 cells. Notably, administration of MLT caused suppression of gastric cancer growth and blockade of tumor angiogenesis in tumor-bearing nude mice. Furthermore, MLT treatment reduced the expression of the MLT nuclear receptor RZR/RORγ, SUMO-specific protease 1, hypoxia-inducible factor-1α and VEGF at transcriptional and translational levels within gastric cancer cells during tumorigenesis. In conclusion, MLT nuclear receptor RZR/RORγ may be of great importance in the MLT mediated anti-angiogenesis and growth-inhibitory effect in gastric cancer cells. Since RZR/RORγ is overexpressed in multiple human cancers, MLT may be a promising agent for the treatment of cancers.