title: A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages.
abstract: The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This allows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.
authors.affiliation: Macro Innovations Ltd, CB4 0DS Cambridge, UK. youcanfindlyn@hotmail.co.uk
authors.forename: Lynda
authors.initials: L
authors.lastname: Thyer
authors.forename: Emma
authors.initials: E
authors.lastname: Ward
authors.forename: Rodney
authors.initials: R
authors.lastname: Smith
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Fiore
authors.forename: Stefano
authors.initials: S
authors.lastname: Magherini
authors.forename: Jacopo J V
authors.initials: JJ
authors.lastname: Branca
authors.forename: Gabriele
authors.initials: G
authors.lastname: Morucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Gulisano
authors.forename: Marco
authors.initials: M
authors.lastname: Ruggiero
authors.forename: Stefania
authors.initials: S
authors.lastname: Pacini
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D016215:Macrophage-Activating Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014807:Vitamin D / Q000494:pharmacology*; D014809:Vitamin D-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D016215:Macrophage-Activating Factors; D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; C101908:vitamin D-binding protein-macrophage activating factor; D014807:Vitamin D