Volume 57, Issue 1 p. 120-129
Original Article

Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells

Sara Proietti

Sara Proietti

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Alessandra Cucina

Alessandra Cucina

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Gabriella Dobrowolny

Gabriella Dobrowolny

IIT, IIT viale Regina Elena 291, Rome, Italy

Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy

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Fabrizio D'Anselmi

Fabrizio D'Anselmi

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Simona Dinicola

Simona Dinicola

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Maria Grazia Masiello

Maria Grazia Masiello

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy

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Alessia Pasqualato

Alessia Pasqualato

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Alessandro Palombo

Alessandro Palombo

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

University of Rome “Tor Vergata”, Rome, Italy

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Veronica Morini

Veronica Morini

Department of Surgery “P. Valdoni”, “Sapienza” University of Rome, Rome, Italy

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Russel J. Reiter

Russel J. Reiter

Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA

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Mariano Bizzarri

Corresponding Author

Mariano Bizzarri

Department of Experimental Medicine, University “La Sapienza”, Rome, Italy

Address reprint requests to Mariano Bizzarri, 14-16, Via Antonio Scarpa, Roma 00161, Italy.

E-mail: [email protected]

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First published: 11 June 2014
Citations: 77

Abstract

Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over-expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome-dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K-AkT-dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2-dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down-regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt-PI3K-dependent MDM2 phosphorylation. Melatonin induces a 3-fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin-treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15-fold increase in p21 levels was observed in melatonin-treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.

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