Distinctive modulation of hepcidin in cancer and its therapeutic relevance

Abstract

Hepcidin, a short peptide synthesized primarily by hepatocytes in response to increased body iron and inflammation, is a crucial iron-regulating factor. Hepcidin regulates intestinal iron absorption and releases iron from macrophages into plasma through a negative iron feedback mechanism. The discovery of hepcidin inspired a torrent of research into iron metabolism and related problems, which have radically altered our understanding of human diseases caused by an excess of iron, an iron deficiency, or an iron disparity. It is critical to decipher how tumor cells manage hepcidin expression for their metabolic requirements because iron is necessary for cell survival, particularly for highly active cells like tumor cells. Studies show that tumor and non-tumor cells express and control hepcidin differently. These variations should be explored to produce potential novel cancer treatments. The ability to regulate hepcidin expression to deprive cancer cells of iron may be a new weapon against cancer cells.

Keywords: cancer; hepcidin; homeostasis; iron; metabolism; therapeutics.

Figure 1

Mechanism regulation hepcidin synthesis in cancer. The liver and local tumor cells in cancer tissue produce hepcidin. Different bone morphogenetic protein (BMP) molecules, including BMP7, and inflammatory triggers, like interleukin-6, are associated with hepcidin overexpression in tumor tissue (IL-6). Studies indicate the presence of novel hepcidin regulators in cancer tissue, including the Wnt pathway and the sclerostin domain-containing protein 1 (SOSTDC1), which is downregulated in cancer due to epigenetic silencing (which is upregulated in cancer). Increased hepcidin in the tumor microenvironment causes ferroportin to behave in a way that causes iron sequestration in tumor cells (FPN). TFR1 overexpression, which increases iron availability to tumor cells, occurs concurrently with an increase in hepcidin. Increased iron depots aid tumor cells in surviving and proliferating.

Figure 2

Factors regulating the expression of hepcidin. Transferrin receptor-1 binds Diferric (Holo) transferrin (TfR1). TfR1 induces HFE to interact with cell-surface-stabilized TfR2. Hepcidin transcription is regulated by the interaction between HFE and TfR2. Sinusoid endothelial cells (SEC) and other non-parenchymal cells produce BMP6 when intracellular iron is present. In order to activate BMP6, hemojuvelin (HJV) interacts with BMPRI-II, a receptor for BMP type I and II. The development of the hepatocyte multiprotein complex promotes the phosphorylation of SMAD1/5/8 and their interaction with SMAD4. The nucleus is where SMAD enters to activate hepcidin. The transmembrane serine protease TMPRSS6, which cleaves membrane HJV and suppresses hepcidin mRNA, is made more active by hypoxia and acute iron deficiency.

Figure 3

Schematic representation of therapeutic treatments targeting hepcidin. Hepcidin antagonists (Pink). Mediators that inhibit hepcidin expression, anti-hepcidin antibodies, or substances that interfere with the interaction between hepcidin and ferroportin. Hepcidin agonists (Blue) Hepcidin analogues and other agents that boost expression of the protein hepcidin.