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

Lynda Thyer,Marco Ruggiero,Massimo Gulisano,Emma Ward,Maria Fiore,Gabriele Morucci,Jacopo Branca,Rodney Smith,Stefano Magherini,Stefania Pacini

doi:10.3390/nu5072577

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 al1ows 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.

Highlights

The so-called vitamin D axis is involved in various aspects of human breast cancer, the most common human tumor
When co-cultured with human breast cancer cells in the absence of GcMAF, macrophages did not interact with human breast cancer cells and their characteristically irregular morphology was maintained (Figure 1A)
Our results demonstrate that GcMAF stimulates macrophages that in turn attack human breast cancer cells, possibly induce their apoptosis and eventually phagocytise them

Summary

Introduction

The so-called vitamin D axis is involved in various aspects of human breast cancer, the most common human tumor. The vitamin D axis is composed of the biologically active form of vitamin D (1,25(OH)(2)D3), and by two proteins that bind it. More intriguing is the relative lack of information about GcMAF and human breast cancer; in the peer-reviewed literature, as of today (May 2013), there are only four studies on this subject. In two of these studies, the effects of GcMAF were observed on the human breast cancer cell line MCF-7 in vitro [3,4]. Another study examined the glycosylation status of vitamin D binding protein in cancer patients including breast cancer patients [5], whereas a less recent study reported the effects of administering GcMAF to metastatic breast cancer patients [6]

Results

Discussion

Conclusion