The mechanism of dysregulated iron homeostasis in cancer cells and the roles of Egr1 and ATF3 in reg
[유방암세포의 비정상적 철분 항상성 조절 기전과 Egr1과 ATF3의 암성장 및 철분대사조절 역할 규명]
Cancer is one of the leading cause of death in the world. According to the WHO, approximately 14 million new cases and 8.2 million cancer related deaths in 2012. Not only in the world, in Korea itself cancer also became the first cause of death (Mortality Data, 2012). One cancer that have high prevalence is breast cancer. Breast cancer showed rapid increase from 20.9% - 44.7% between 1999 - 2012 (Cancer Statistic Korea).
Iron, one of the micronutrient, is well known as a part of hemoglobin that function as oxygen carrier inside our body. Besides, the availability of iron inside the cell is important for cell growth and proliferation because this micronutrient is responsible for the generation of enzyme that important for deoxynucleotide production. However, excess iron induces oxidative stress and DNA damage. Iron overload also being associated with some health problem such as cirrhosis, cardiac arrhythmyas, cancer and diabetes.
Our laboratory studies about iron homeostasis in cancer cell, especially in breast cancer cells. In some previous studies, it was found that cancer cell need higher levels of iron. To fulfill the its necessity for iron, cancer cell exhibit iron deplete cell phenotypes by express high level of iron uptake protein (TfR1), also by lower the expression of iron storage protein (Ferritin) and iron exporter (Ferroportin).
In our previous study, we found out that Egr1 and ATF3 were overexpressed in DFO induced-iron depletion condition (1). DFO treatment in hepatoma cells showed to lower reactive oxygen species (ROS) production and increased caspase 3/7 activity and cell death. We found out that DFO-induced iron deficiency upregulates Egr1 in part through transcriptional activation via ERK and Elk-1 signals, which may be important in the regulation of cell death in hepatoma cells.
Targeting iron metabolism in cancer cells will take advantages to decide target genes for cancer treatment. Right now, we aim to get better idea how cancer cells regulates the expression of iron-homeostasis-related genes to take up more iron than normal cells and we also try to reveal the role of Egr1 and ATF3 in the regulation of cancer growth as well as iron metabolism.
Fig 1. Iron homeostasis in normal and cancer cell
(1) Lee SM, Lee SB, Prywes R, Vulpe CD: Iron deficiency upregulates Egr1 expression. Genes Nutr 2015, 10:468.