Melatonin induces cell apoptosis in renal carcinoma cells via regulating mitochondria function, promoting ROS production, and suppression of Akt/mTOR/S6K signaling pathway

Abstract Purpose In recent years, metabolic alteration has been identified as a driver in the development of renal cell carcinoma (RCC), which plays a critical role in cancer cells to adapt to hypoxic environment and cell proliferation. Melatonin (MLT), a neurohormone secreted during the dark hours by the vertebrate pineal gland, induces metabolic reprogramming in cancer cells by suppression of aerobic glycolysis. Whether it can be used as a potential therapeutic tool in RCC is worth exploring. Methods In this study, we detected concentration of metabolites in RCC cells through metabo-lomic analyses using UPLC-MS/MS and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer. Results We found that MLT significantly inhibited proliferation and induced apoptosis in RCC cells, moreover, MLT increased ROS level and inhibited the activity of antioxidant enzymes. Furthermore, MLT up-regulated key TCA cycle metabolites while reduced aerobic glycolysis products, and induced higher oxygen consumption rate, more ATP production, and higher membrane potential in RCC cells, indicating that MLT enhances mitochondrial function and re-vert aerobic glycolysis to mitochondrial OXPHOS in RCC cells. Moreover, MLT treatment inhibited the phosphorylation levels of Akt, mTOR, and p70 S6 Kinase in RCC cells, while the application of NAC (inhibitors of ROS) not only restored the phosphorylation of these proteins but also decreased cell apoptosis. Consistently, MLT treatment significantly inhibited growth of RCC cell xenografts in nude mice. Conclusion Our results indicate that MLT treatment promotes intracellular ROS production via metabolic reprogramming and reducing antioxidants, which suppressed the activity of Akt/mTOR/S6K signaling pathway and induced apoptosis in RCC cells.