Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation.
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.
Molecular Chemoprevention Group, Molecular Medicine Area, Regina Elena National Cancer Institute, Rome 00144, Italy.
Raffaela
R
Santoro
Federica
F
Mori
Marina
M
Marani
Giuseppe
G
Grasso
Maria Anna
MA
Cambria
Giovanni
G
Blandino
Paola
P
Muti
Sabrina
S
Strano
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D053517:Matrix Metalloproteinase 15 / Q000235:genetics / Q000378:metabolism; D008550:Melatonin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D044094:Receptors, Melatonin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C507098:MMP15 protein, human; D043562:Receptors, G-Protein-Coupled; D044094:Receptors, Melatonin; D016159:Tumor Suppressor Protein p53; D053517:Matrix Metalloproteinase 15; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D008550:Melatonin