Vitamin D-Mediated Anti-cancer Activity Involves Iron Homeostatic Balance Disruption and Oxidative Stress Induction in Breast Cancer

Asima Karim,Khuloud Bajbouj,Abeer Al-Ali,Jibran Sualeh Muhammad,Lina Sahnoon,Salman Y Guraya,Mawieh Hamad,Jasmin Shafarin

doi:10.3389/fcell.2021.766978

Asima Karim, Khuloud Bajbouj + Show 6 more

Open Access

https://doi.org/10.3389/fcell.2021.766978

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Abstract

Background: Vitamin D deficiency associates with high risk of breast cancer (BRCA) and increased cellular iron. Vitamin D exerts some of its anti-cancer effects by regulating the expression of key iron regulatory genes (IRGs). The association between vitamin D and cellular iron content in BRCA remains ambiguous. Herein, we addressed whether vitamin D signaling exerts a role in cellular iron homeostasis thereby affecting survival of breast cancer cells.Methods: Expression profile of IRGs in vitamin D-treated breast cancer cells was analyzed using publicly available transcriptomic datasets. After treatment of BRCA cell lines MCF-7 and MDA-MB-231 with the active form of vitamin D, labile iron content, IRGs protein levels, oxidative stress, and cell survival were evaluated.Results: Bioinformatics analysis revealed several IRGs as well as cellular stress relates genes were differentially expressed in BRCA cells. Vitamin D treatment resulted in cellular iron depletion and differentially affected the expression of key IRGs protein levels. Vitamin D treatment exerted oxidative stress induction and alteration in the cellular redox balance by increasing the synthesis of key stress-related markers. Collectively, these effects resulted in a significant decrease in BRCA cell survival.Conclusion: These findings suggest that vitamin D disrupts cellular iron homeostasis leading to oxidative stress induction and cell death.

Highlights

It is well-established that potent forms of vitamin D, mainly 1,25-dihydroxycholecalciferol, play important roles in human development and physiology, especially in bone metabolism and the regulation of calcium and phosphorus levels
Vitamin D Differentially Alters the Expression Profile of Iron Regulatory Genes To investigate the effect of vitamin D on breast cancer cells, we first performed in silico analysis of a publicly available expression array dataset of breast cancer cells treated with 40–50 μM of calcitriol
Disruption of iron metabolism and induction of oxidative stress is known to induce a deleterious effect on cancer cells

Summary

Introduction

It is well-established that potent forms of vitamin D, mainly 1,25-dihydroxycholecalciferol, play important roles in human development and physiology, especially in bone metabolism and the regulation of calcium and phosphorus levels. It was reported that vitamin D can upregulate the expression of p21WAF 1/Cip 1 and p27Kip 1 which are the cell cycle regulators limiting the proliferative potential of cancer cells (Gartel and Tyner, 2002; Audo et al, 2003). In vitro studies stated that vitamin D has the ability of BRCA cell lines inhibition as well as induction of apoptosis by upregulating the expression of p21WAF1/Cip, p53, and Bax (caspase activator) genes and by reducing the expression of Bcl-2 (anti-apoptotic mediator) (Calvert et al, 1998; Gartel and Tyner, 2002; Audo et al, 2003). We addressed whether vitamin D signaling exerts a role in cellular iron homeostasis thereby affecting survival of breast cancer cells

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