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

Sara Proietti, Alessandra Cucina, Gabriella Dobrowolny, Fabrizio D'Anselmi, Simona Dinicola, Maria Grazia Masiello, Alessia Pasqualato, Alessandro Palombo, Veronica Morini, Russel J Reiter, Mariano Bizzarri

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)120-129
Number of pages10
JournalJournal of Pineal Research
Volume57
Issue number1
DOIs
StatePublished - 2014

Fingerprint

MCF-7 Cells
Melatonin
Acetylation
Down-Regulation
Gene Expression
Phosphatidylinositol 3-Kinases
Growth
Phosphorylation
Apoptosis
Ubiquitin-Protein Ligases
Nuclear Envelope
Proteasome Endopeptidase Complex
Cytosol
Neoplasms
Breast Neoplasms

Keywords

  • AkT
  • MDM2
  • MDMX
  • melatonin
  • p300
  • p53-acetylation
  • Sirt1

ASJC Scopus subject areas

  • Endocrinology
  • Medicine(all)

Cite this

Proietti, S., Cucina, A., Dobrowolny, G., D'Anselmi, F., Dinicola, S., Masiello, M. G., ... Bizzarri, M. (2014). Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. Journal of Pineal Research, 57(1), 120-129. https://doi.org/10.1111/jpi.12150

Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. / Proietti, Sara; Cucina, Alessandra; Dobrowolny, Gabriella; D'Anselmi, Fabrizio; Dinicola, Simona; Masiello, Maria Grazia; Pasqualato, Alessia; Palombo, Alessandro; Morini, Veronica; Reiter, Russel J; Bizzarri, Mariano.

In: Journal of Pineal Research, Vol. 57, No. 1, 2014, p. 120-129.

Research output: Contribution to journalArticle

Proietti, S, Cucina, A, Dobrowolny, G, D'Anselmi, F, Dinicola, S, Masiello, MG, Pasqualato, A, Palombo, A, Morini, V, Reiter, RJ & Bizzarri, M 2014, 'Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells', Journal of Pineal Research, vol. 57, no. 1, pp. 120-129. https://doi.org/10.1111/jpi.12150
Proietti S, Cucina A, Dobrowolny G, D'Anselmi F, Dinicola S, Masiello MG et al. Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. Journal of Pineal Research. 2014;57(1):120-129. https://doi.org/10.1111/jpi.12150
Proietti, Sara ; Cucina, Alessandra ; Dobrowolny, Gabriella ; D'Anselmi, Fabrizio ; Dinicola, Simona ; Masiello, Maria Grazia ; Pasqualato, Alessia ; Palombo, Alessandro ; Morini, Veronica ; Reiter, Russel J ; Bizzarri, Mariano. / Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. In: Journal of Pineal Research. 2014 ; Vol. 57, No. 1. pp. 120-129.
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