Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities

Abstract

Excess iron is tightly associated with tumorigenesis in multiple human cancer types through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, regulating DNA replication, repair and cell cycle progression, affecting signal transduction in cancer cells, and acting as an essential nutrient for proliferating tumor cells. Thus, multiple therapeutic strategies based on iron deprivation have been developed in cancer therapy. During the past few years, our understanding of genetic association and molecular mechanisms between iron and tumorigenesis has expanded enormously. In this review, we briefly summarize iron homeostasis in mammals, and discuss recent progresses in understanding the aberrant iron metabolism in numerous cancer types, with a focus on studies revealing altered signal transduction in cancer cells.

Introduction: overview of iron and cancer

Iron serves important functions for mammalian cells as it is involved in cell proliferation, metabolism and growth (Torti and Torti, 2013). These processes are controlled by a variety of iron- and heme-containing proteins, including enzymes involved in DNA stability and cell cycle progression, mitochondrial enzymes involved in respiratory complexes, and detoxifying enzymes such as peroxidase and catalase (Torti and Torti, 2013; Zhang, 2014). Within the human body, iron biologically exists in two oxidation states: ferrous iron (Fe²⁺) and ferric iron (Fe³⁺) (Pantopoulos et al., 2012; Rouault, 2003). Iron has the property of gaining and losing electrons, which enables it to participate in Fenton reaction (Pantopoulos et al., 2012; Torti and Torti, 2013), in which Fe²⁺ donates an electron in a reaction with hydrogen peroxide (H₂O₂) to produce the hydroxyl radical (^•HO) (Thomas et al., 2009), a reactive oxygen species (ROS). Human body needs to maintain systemic and cellular iron homeostasis by regulating iron acquisition, storage and efflux (Zhang, 2014). Iron homeostasis is not only required for iron-containing protein functions, but also critical for signal transduction and cellular microenvironment (**ong et al., 2014). The elevated iron may result in the generation of ROS, which can damage lipids, proteins and DNA, eventually leading to tumorigenesis (Orrenius et al., 2011; Romero et al., 2014). It has been reported that numerous types of cancers are implicated by iron, such as lung cancer, breast cancer, prostate cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer and hematological malignancies (Fig. 1) (Torti and Torti, 2013). On the other hand, iron deficiency caused anemia is one of the major public health problems, particularly in children and pregnant women (Denic and Agarwal, 2007; Miller, 2013). The recent studies also indicate that many patients with cancer have anemia (Munoz et al., 2014), but the cause is still to be determined.

Figure 1

Iron is implicated in multiple cancer types. These cancers mainly include breast cancer, lung cancer, prostate cancer, pancreatic cancer, melanoma, bladder cancer, hepatocellular cancer, colorectal cancer, gastric cancer and haematological cancers

Previous studies suggest that iron may function in tumour initiation, tumour growth, tumour microenvironment and metastasis (Mantovani et al., 2008; Sica et al., 2008). In cancer cells, pathways involved in iron acquisition, trafficking, storage and regulation are all perturbed, suggesting that iron metabolism is important for tumour cell survival (Torti and Torti, 2013). Additionally, iron can also contribute to DNA replication and repair processes, as well as cell cycle control in cancer cells (Torti and Torti, 2013; Zhang, 2014). Signalling through p53, Wnt, hypoxia-inducible factor (HIF), DNA replication, repair and cell cycle progression pathways may associate with altered iron metabolism in cancer (Torti and Torti, 2013). Thus, decreasing cellular iron levels, targeting iron metabolic pathways and iron-containing proteins may provide new tools for cancer therapy.

Iron metabolism in mammals

Mammalian organisms have evolved sophisticated mechanisms to regulate systemic and cellular iron balance (Andrews and Schmidt, 2007; Pantopoulos et al., 2012).

Systemic iron metabolism

Generally, systemic iron regulatory processes include several critical steps: (1) duodenal enterocytes acquire dietary iron via divalentmetal transporter 1 (DMT1), also known as solute carrier family 11 member 2 (SLC11A2), natural resistance-associated macrophage protein 2 (NRAMP2), or divalent cation transporter (DCT1) (Pantopoulos et al., 2012). DMT1 localizes on the apical surface and functions dependently on the reduction of Fe³⁺ to Fe²⁺ by duodenal cytochrome b (DcytB) (Pantopoulos et al., 2012); (2) spleenic reticuloendothelial macrophages are responsible for iron recycling from senescent red blood cells (Pantopoulos et al., 2012); (3) iron exporter ferroportin (Fpn) releases iron oxidized prior by hephaestin from Fe²⁺ to Fe³⁺ (Pantopoulos et al., 2012); (4) transferrin (Tf) located on plasma membrane acquires and delivers iron in the body (Pantopoulos et al., 2012); and (5) hepatic hormone hepcidin controls systemic iron trafficking and iron efflux from cells by regulating Fpn stability (Pantopoulos et al., 2012; Zhang, 2014).

Cellular iron metabolism

Cellular iron homeostasis is controlled by iron uptake at the plasma membrane, eliciting balanced iron distributions among cellular compartments and iron export (Valerio, 2007; Zhang, 2014). Briefly, most mammalian cells acquire iron via Tf to form holo-Tf (Anderson and Vulpe, 2009; Dunn et al., 2007), which further binds to transferrin receptor 1 (TfR1) to form holo-Tf-TfR1 complex on the iron-consuming cell membrane (Zhang, 2014). This complex is subsequently internalized by receptor-mediated endocytosis (Lill et al., 2012) and acidified in the endosome, facilitating the release of Fe³⁺ from holo-Tf (Zhao et al., 2010). The six-transmembrane epithelial antigen of the prostate 3 (Steap3) reduces Fe³⁺ to Fe²⁺, followed by transporting Fe²⁺ into the cytoplasm by DMT1 or transient receptor potential protein (TRPML1) (Zhang et al., 2012). Later, the holo-Tf-TfR1 complex disassembles and apo-Tf recycles back to the cell membrane to repeat another cycle (Pantopoulos et al., 2012). Thereafter, the newly acquired iron stores into the cytosolic “labile iron pool” (Gkouvatsos et al., 2012; Pantopoulos et al., 2012). The excess cellular iron is either stored in ferritin or exported via Fpn (Pantopoulos et al., 2012) (Fig. 2). Moreover, two iron regulatory proteins, namely, IRP1 and IRP2, can post-transcriptionally regulate cellular iron homeostasis (Zhang, 2014). In low iron condition, IRP1 and IRP2 proteins specifically bind to iron-responsive elements (IRE) in 3′- or 5′-UTR of the mRNA transcripts in TfR1, ferritin heavy (H) chain, ferritin light (L) chain, or DMT1 (Zhang, 2014). The IRE-IRP system functions importantly in the control of mammalian iron homeostasis (Pantopoulos et al., 2012). Consequently, these iron regulatory proteins are protected from degradation or their translations are inhibited (Anderson and Vulpe, 2009; Dunn et al., 2007; Kaplan and Kaplan, 2009; Muckenthaler et al., 2008).

Figure 2

Cellular iron metabolism in mammals. Apo-Tf binds ferric iron to form holo-Tf. Holo-Tf further forms a complex with TfR1 on the cell surface and the complex undergoes endocytosis. Acidifying by a proton pump, ferric iron is released from holo-Tf in the endosome, where Steap3 reduces ferric iron to ferrous iron. Further, ferrous iron is transported across the endosomal membrane to the cytosol by DMT1. DMT1 also facilitates dietary ferrous iron absorption in the plasma. The released apo-Tf is recycled back to the plasma membrane to repeat another cycle. Newly acquired iron enters into cytosolic “labile iron pool” (LIP) (Pantopoulos et al., 2012). The LIP is utilized by iron-sulfur clusters (Fe-S) proteins, hemoproteins, RNR and other iron-containing proteins, which localize in different cellular compartments (Zhang, 2014). Cellular iron that is not utilized is either stored in ferritin or exported via ferroportin (Pantopoulos et al., 2012)

Iron is implicated in a variety of cancer types

Multiple cancer types have been widely reported to exhibit abnormal iron contents or deficiency in iron uptake, utilization and storage (Fig. 3). These cancers mainly include lung cancer, breast cancer, prostate cancer, colorectal cancer, hepatocellular cancer, pancreatic cancer, haematological cancers, renal cell carcinoma and melanoma (Fig. 1) (Torti and Torti, 2013).

Figure 3

Iron metabolism in normal cell and cancer cell. (A) The expression of Tf, TfR1, TfR2 and hepcidin is low, whereas the expression of iron exporter gene FPN is high in normal cells, leading to a small pool of labile iron (Torti and Torti, 2013). (B) Cancer cells exhibit increased expression of TfR1 and hepcidin, but low levels of FPN, leading to an increased labile iron pool (Torti and Torti, 2013)

Lung cancer

Lung cancers are generally categorized as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (Vescio et al., 1990). During the past few years, hepcidin and several iron metabolism related proteins have been demonstrated to associate with lung cancer genesis and tumor cell proliferation (**ong et al., 2014). Hepcidin expression is increased in tumor tissue and serum of NSCLC patients, and the increased serum hepcidin level is associated with lymph node metastasis and tumor clinical stage of NSCLC (**ong et al., 2014). Iron related proteins, such as TfR1, H and L subunits of ferritin protein, also exhibit increased levels in lung cancer. In H1299 lung cancer cells, the induction of p53 decreases iron regulatory protein binding, leading to an increase in both H and L subunits of ferritin protein, but a decline of TfR1 level (Zhang et al., 2008). However, some studies reported elevated expression of TfR1 in NSCLC patients (Kukulj et al., 2010; **ong et al., 2014). The elevated serum ferritin levels were observed in NSCLC and SCLC patients (Aleman et al., 2002; Kukulj et al., 2010; Yildirim et al., 2007), and in patients with cancer during radiotherapy (Koc et al., 2003). However, the expression of FPN in lung cancer cells has not been reported.

IRP1 is responsible for cytosolic iron concentrations and can post-transcriptionally regulate the expression of iron metabolism genes to maintain cellular iron homeostasis (Rouault, 2006). In cells with iron deficiency, IRP1 can bind to IRE element of ferritin mRNA, enhancing iron uptake and decreasing iron sequestration (Rouault, 2006). The tetracycline-inducible overexpression of IRP1 or IRP1 _C437S mutant results in misregulation of iron metabolism, highly active in IRE-binding and increased TfR1 levels in human H1299 lung cancer cells (Wang and Pantopoulos, 2002), but not altering the growth properties of the H1299 cells invitro (Wang and Pantopoulos, 2002). However, overexpression of IRP1 or IRP1 _C437S dramatically suppresses the growth of tumor xenografts in nude mice (Chen et al., 2007), providing a direct regulatory link between the IRE/IRP system and cancer. In A549 lung cancer cells, IRP2 can regulate the expression of TfR1 and ferritin by changing its own gene expression, and thereby regulating iron metabolism (Cheng et al.,

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Acknowledgments

We apologize to all authors whose contributions were not cited due to space limitations. We would like to express our gratitude to Dr. Jianbin Wang for critically reading the manuscript and for facilitating discussions.

Compliance with ethics guidelines

Caiguo Zhang and Fan Zhang declare no conflict of interest.

This article does not contain any studies with human or animal as subjects performed by the authors.

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Authors and Affiliations

1. Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, 80045, USA

   Caiguo Zhang

2. Orthopedics Department, Changhai Hospital Affiliated to Second Military Medical University, Shanghai, 200433, China

   Fan Zhang

Corresponding author

Correspondence to Caiguo Zhang.

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Zhang, C., Zhang, F. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities. Protein Cell 6, 88–100 (2015). https://doi.org/10.1007/s13238-014-0119-z

• Received: 16 October 2014

• Accepted: 04 November 2014

• Published: 06 December 2014

• Issue Date: February 2015

• DOI: https://doi.org/10.1007/s13238-014-0119-z

Keywords