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.
Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation / R. Santoro, F. Mori, M. Marani, G. Grasso, A.M. Cambria, G. Blandino, P. Muti, S. Strano. - In: CARCINOGENESIS. - ISSN 0143-3334. - 34:5(2013), pp. 1051-1061.
|Titolo:||Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation|
MUTI, PAOLA CORNELIA MARIA (Penultimo) [Conceptualization]
|Parole Chiave:||SiRNA; Small interfering RNA; Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; HCT116 Cells; Humans; MCF-7 Cells; Matrix Metalloproteinase 14; Matrix Metalloproteinase 15; Melatonin; Mice; Mice, Nude; Receptors, G-Protein-Coupled; Receptors, Melatonin; Transplantation, Heterologous; Tumor Suppressor Protein p53; DNA Damage|
|Settore Scientifico Disciplinare:||Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica|
|Data di pubblicazione:||2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/carcin/bgt025|
|Appare nelle tipologie:||01 - Articolo su periodico|
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