title: Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells.
abstract: Melatonin and vitamin D3 inhibit breast cancer cell growth and induce apoptosis, but they have never been combined as a breast cancer treatment. Therefore, we investigated whether their association could lead to an enhanced anticancer activity. In MCF-7 breast cancer cells, melatonin together with vitamin D3, induced a synergistic proliferative inhibition, with an almost complete cell growth arrest at 144 hr. Cell growth blockade is associated to an activation of the TGFβ-1 pathway, leading to increased TGFβ-1, Smad4 and phosphorylated-Smad3 levels. Concomitantly, melatonin and D3, alone or in combination, caused a significant reduction in Akt phosphorylation and MDM2 values, with a consequent increase of p53/MDM2 ratio. These effects were completely suppressed by adding a monoclonal anti-TGFβ-1 antibody to the culture medium. Taken together, these results indicate that cytostatic effects triggered by melatonin and D3 are likely related to a complex TGFβ-1-dependent mechanism, involving down-regulation of both MDM2 and Akt-phosphorylation.
authors.affiliation: Department of Experimental Medicine, University La Sapienza, Roma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Proietti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cucina
authors.forename: Fabrizio
authors.initials: F
authors.lastname: D'Anselmi
authors.forename: Simona
authors.initials: S
authors.lastname: Dinicola
authors.forename: Alessia
authors.initials: A
authors.lastname: Pasqualato
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lisi
authors.forename: Mariano
authors.initials: M
authors.lastname: Bizzarri
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002762:Cholecalciferol / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D053773:Transforming Growth Factor beta1; D002762:Cholecalciferol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin