Role of Endoplasmic Reticulum Stress in Melatonin-induced Apoptosis and Inhibition of Invasion and Migration in Adrenocortical Carcinoma Cells.

Background: Melatonin, a hormone synthesized by the pineal gland and released into the blood, seems to have anti-tumor properties. However, the mechanisms of the anti-cancer effect of melatonin are largely unknown. This study investigated the anti-tumor activity of melatonin in adrenocortical carcinoma (ACC) and analyzed its molecular mechanisms.

Methods: Different concentrations of melatonin were added to ACC cells in vitro and in vivo. Cell viability was appraised via Cell Counting Kit-8 (CCK-8) assay, cell migration and invasion were appraised via wound healing assay and transwell assay, and cell apoptosis was appraised via flow cytometry. The levels of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (MAPK) pathway proteins (c-Jun N-terminal kinase (JNK) and p38) and endoplasmic reticulum stress-related proteins (C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78)) were appraised via western blot.

Results: Melatonin reduced the proliferation rate, migration rate, and invasion rate of ACC cells, and significantly increased apoptosis of ACC cells in contrast with the Control Check (CK) group. Moreover, melatonin intervention reduced NF-κB/MAPK signal routing (JNK and p38) and endoplasmic reticulum stress (CHOP and GRP78). Treatment with the NF-κB/MAPK pathway inhibitor NF-κB/MAPK-IN-1 (3.48 μM) enhanced the inhibitory effects of melatonin on the activity of ACC cells and increased apoptosis. The subcutaneous tumor model (SW-13) in nude mice further confirmed that melatonin induced apoptosis of ACC cells by reducing endoplasmic reticulum stress, and NF-κB/MAPK signal routing was involved in this effect.

Conclusion: Melatonin induces apoptosis of ACC cells by reducing endoplasmic reticulum stress, and this effects was may be related to the NF-κB/MAPK signal routing. Melatonin may be an effective anti-tumor agent and have great potential as an adjuvant therapy in the future.