Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation

• Published in: Carcinogenesis (New York) 2013-05, Vol.34 (5), p.1051-1061
• Main Authors: Santoro, Raffaela, Mori, Federica, Marani, Marina, Grasso, Giuseppe, Cambria, Maria Anna, Blandino, Giovanni, Muti, Paola, Strano, Sabrina
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; DNA Damage; HCT116 Cells; Humans; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Matrix Metalloproteinase 15 - genetics; Matrix Metalloproteinase 15 - metabolism; MCF-7 Cells; Melatonin - genetics; Melatonin - metabolism; Melatonin - pharmacology; Mice; Mice, Nude; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Melatonin - antagonists & inhibitors; Receptors, Melatonin - genetics; Receptors, Melatonin - metabolism; Transplantation, Heterologous; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgt025

Melatonin has been known to be a chemopreventive agent since its levels inversely correlate with the risk of developing cancer. We have recently shown that melatonin induces p38-dependent phosphorylation of both p53 and histone H2AX. This is associated with a p53-mediated increase in repair of both endogenous and chemotherapy-induced DNA damage. In addition, the inhibition of p38 activities impairs melatonin's capability to induce a p53-dependent DNA damage response and thus its ability to maintain genome integrity. Since melatonin-induced p53 phosphorylation requires an intact p38 phosphorylation cascade and p38 can be activated by G proteins, we supposed that melatonin's activities could be mediated by its G-protein-coupled membrane receptors, MT1 and MT2. Here, we show that the activation of the p53-dependent DNA damage response by melatonin is indeed mediated by MT1 and MT2. As a result, the absence of either receptor impairs melatonin's ability to reduce both cell proliferation and clonogenic potential of cancer cells. In addition, this causes an impairment of the p53-dependent DNA damage response. By providing molecular insight, our findings might have translational impact, suggesting the involvement of melatonin receptors in tumorigenesis.