Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function

Abstract

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.

Melatonin and verteporfin synergistically suppress the growth and stemness of head and neck squamous cell carcinoma through the regulation of mitochondrial dynamics

“…Other previous studies reported that Mel prevents mitochondrial damage and reduces mitochondrial ROS level in various diseases caused by oxidative stress. 51,52 On the contrary, a study by Guerra-Librero et al 53 proposed that Mel induces mitochondrial respiration and glycolytic capacity, resulting in the increase in mitochondrial ROS level and cell death in HNSCCs. Consistent with the study, our results showed that Mel caused a substantial increase in mitochondrial ROS level, which is known to induce apoptosis, cell cycle arrest, and senescence in cancer cells.…”

Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

“…Last but not least, melatonin affected cancer metabolism in Cal-27 and SCC-9 head and neck squamous cell carcinoma (HNCC) cells by regulating mitochondrial function and structure. Melatonin stimulated OXPHOS and suppressed cytosolic aerobic glycolysis leading to ROS production, mitophagy, apoptosis and reduction of cell proliferation [ 113 ].…”

Molecular Subtypes Based on Cell Differentiation Trajectories in Head and Neck Squamous Cell Carcinoma: Differential Prognosis and Immunotherapeutic Responses

“…Studies have also shown that glucose metabolism plays an important role in the occurrence and development of HNSCC. For example, metformin is associated with the prevention of HNSCC (42,43). Some important metabolic pathways in our study were tryptophan metabolism, primary bile acid biosynthesis, alpha linoleic acid metabolism, and N-glycan biosynthesis.…”