The anti-cancer effects of melatonin on oral squamous cell carcinoma : the scientific basis and clinical implication

Abstract

Oral squamous cell carcinomas (OSCCs) are one of the most prevalent malignancies throughout the world, with poor prognosis and low 5-year survival rate. Novel effective drugs and treatment methods are highly required to improve the outcomes of OSCCs patients. Melatonin is an endogenous hormone with various functions on human pathology and physiology such as antioxidant, anti-inflammation and immunomodulatory. Recent evidence has made melatonin a promising adjunctive method for the prevention and treatment of OSCCs, whereas the detailed mechanisms underlying its anticancer effects need more investigations. The aim of this project is to identify the oncostatic properties of melatonin and further explore the underlying mechanisms and its potential application with other anti-cancer agents. Accordingly, this study extended to investigate i) the direct inhibitory effects of melatonin on cancer cells and the possible signaling pathways involved, ii) how melatonin regulates the immune system in the tumor microenvironment and iii) the effects of melatonin on the ROS metabolism of oral cancer cells and the potential synergistic anti-cancer effects of melatonin and ferroptosis inducer (erastin). Notably, Exogenous hFGF19 eliminated the inhibitory effects of melatonin on SCC-15 invasion and migration, while FGF19 knocking-down showed similar inhibitory activities with melatonin. Herein, melatonin suppresses SCC-15 invasion and migration through blocking FGF19/FGFR4 pathway. Next, SCC-15 cells co-cultured with THP-1 cells/MDMs exhibited increased migration and invasion capabilities. Melatonin inhibited the increased expression of MIF in the co-culture system and IL-1β in the co-cultured THP-1 cells/MDMs. Moreover, the IL-1β secretion in THP-1 cells/MDMs is MIF and NLRP3 dependent and IL-1β increased the invasion and migration capabilities of SCC-15 cells. These results demonstrated that THP-1 cells/MDMs facilitated the progression of SCC-15 cells by promoting the MIF/NLRP3/IL-1β loop, which could be interrupted by melatonin. Thus, melatonin could act as an alternative anticancer agent for OSCCs treatment by tackling the MIF/NLRP3/IL-1β loop. Furthermore, cellular ROS was induced by a high level (mM) of melatonin, The combination of melatonin with erastin enhanced the level of Malonic dialdehyde, ROS and lipid ROS, and reduced the level of glutamate and glutathione. SQSTM1/p62, LC3A/B, cleaved caspase-3 and PARP1 protein levels in SCC-15 cells were increased by melatonin + erastin as well, which were further up-regulated as ROS accumulation and down-regulated as ROS decreased. Melatonin combined with erastin remarkably reduced the tumor size in vivo and demonstrated no obvious systemic side effects, and significantly enhanced the apoptosis and ferroptosis levels in the tumor tissues, accompanied with decreased autophagy levels. In conclusion, the current findings provide the first evidence that melatonin suppresses SCC-15 invasion and migration through blocking FGF19/FGFR4 pathway and interrupts the macrophage-induced progression of SCC-15 cells by tackling the MIF/NLRP3/IL-1β loop. The synergistic combination of melatonin and erastin exhibits promising anticancer effects without adverse reactions. This pioneering study enriches our understanding on the role of melatonin in the prevention and management of OSCCs, thereby contributing to developing novel strategies to combat OSCCs.