Fig. 4

Oncosuppressive mechanisms mediated by melatonin. Melatonin (MLT) activates the high-affinity G protein-coupled receptors MT1 and MT2 which reduce the transcriptional activity of NF-κB and activates phosphorylation cascades mediated by mitogen-activated protein kinases (MAPKs) including MEK1/2, ERK1/2, JNK, and p38. In turn, NF-κB inhibition and MAPKs activation inhibit cell growth and motility and promote apoptosis and DNA damage repair through accumulation of oncosuppressors such as p53, p27kip1, and p21. NF-κB inhibition and MAPKs activation also activates DNA repair complexes such as P53/PML/H2AX on DNA damage sites, and transcriptional control of genes involved in the cell cycle, apoptosis, and invasiveness. Further, melatonin can bind to the intracellular protein calmodulin (CaM) and reduce the Estrogen Receptor α (Erα) response in ER positive cells by impairing the formation of a proper E2–Erα–CaM complex on target genes. Melatonin downregulates the nuclear RZR receptors (RZR alpha, RZR beta, ROR alpha 1, RZR alpha 2, ROR alpha 3 and ROR gamma), inhibiting growth, angiogenesis and HIF-1α activity. Arrows indicate activation, while dashed blunt lines indicate inhibition. Activation indicates an increase in protein or activity levels, while inhibition indicates a decrease in protein or activity levels