Orexin A upregulates the protein expression of OX1R and enhances the proliferation of SGC-7901 gastric cancer cells through the ERK signaling pathway

Abstract

Orexins are hypothalamic peptides that regulate food intake, wakefulness, the reward system and energy metabolism. Recent studies have demonstrated the ability of orexins to promote a robust apoptosis and subsequent inhibition of cell growth in various types of cancer cells. The present study was conducted to investigate the effects of orexin A on the survival of human gastric cancer cells, SGC‑7901, and the possible mechanisms. SGC‑7901 cells were exposed to various concentrations of orexin A in vitro in the presence or absence of the orexin receptor 1 (OX1R) antagonist (SB334867), extracellular signal‑regulated kinases 1 and 2 (ERK1/2) antagonist (U0126) or a combination of the two antagonists. The amount of cell proliferation, viability and apoptosis, caspase‑8 and caspases‑9 activities, OX1R protein expression and ERK1/2 protein levels were determined. The expression of OX1R in SGC‑7901 cells was observed. Orexin A (10-10 to 10-6 M) stimulated SGC‑7901 cell proliferation and viability, reduced the pro‑apoptotic activity of caspase‑9 and protected the cells from apoptosis in a dose‑dependent manner. Additionally, ERK1/2 phosphorylation was stimulated by orexin A (10-10 to 10-6 M). However, the OX1R antagonist SB334867 (10-6 M), ERK1/2 antagonist U0126 (30 µM) or the combination of antagonists blocked the effects of orexin A to a certain extent. These results suggest that stimulation of OX1R induces the growth of SGC‑7901 gastric cancer cells through activation of ERK1/2 signaling pathway. These findings add a new dimension to the biological activities of orexin, which may have important implications in health and disease, in particular gastric cancer.

The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role

“…OX1R was also identified in cortical adenomas but its relation to apoptosis was not investigated ( 88 , 89 ). In human hepatocellular carcinoma tissues ( 90 ), in gastric cancer cell lines, SGC-7901 and BGC-823, OxA seemed to enhance the proliferation and inhibited the apoptosis which is mediated by the ERK or AKT signaling pathway ( 91 , 92 ), respectively. Moreover, OxA and cholecystokinin (CCK) inhibited the migration of colorectal cancer cell line, HT-29 mediated by heterodimerization of OX1R and CCK1R ( 93 ).…”

A review of orexin’s unprecedented potential as a novel, highly-specific treatment for various localized and metastatic cancers

“…OX1R mRNA was expressed in the following cell lines: BGC-823 12 and SGC-7901. 13 OX2R mRNA was not expressed in either of these cell lines. 12 , 13 …”

Original Research: Orexins A and B stimulate proliferation and differentiation of porcine preadipocytes

“…However, recent results showed that OXA can enhance proliferation of rat insulinoma or SGC-7901 human cancer gastric cells. 27,29,30 Noteworthy, in all studies, orexin concentrations as well as times of incubations were very similar. Overall, stimulation of cell death in cancer cells is not general, and cell specific effects of OXA may be possible.…”