Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane

Izumi, Yasukatsu; Yasui, Yumiko; Noguchi, Yasuhisa; Kishi, Fumio

doi:10.1002/cbin.10403

Cited by 14 publications

(17 citation statements)

References 33 publications

(44 reference statements)

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“…Although the inhibitory effect of ferristatin was at first attributed to degradation of TfR1196, subsequent work demonstrated that ferristatin directly inhibited activity of DMT1195. Similarly, ferristatin II is a structurally unrelated compound that has shown potent TfR1-inhibiting properties, mediated via DMT1 internalization, in vitro , as well as in vivo 197,198. Interestingly, ferristatin II also induces hepcidin expression via JAK/STAT3 signalling in vivo 199.…”

Section: Iron Metabolism As a Therapeutic Targetmentioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

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Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

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Section: Iron Metabolism As a Therapeutic Targetmentioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

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“…Initially identified in a screen for the inhibition of transferrin-mediated iron delivery, ferristatin II was shown to induce the degradation of transferrin receptor 1, thus reducing the cellular import of transferrin-bound iron. More recently, it has been shown to induce DMT1 internalisation and thereby reduce the uptake of non-haem iron [37]. A third mode of action is its ability to upregulate the synthesis of the peptide hormone hepcidin, which acts as negative regulator of iron uptake through the initiation of the degradation of the iron exporter ferroportin [38,39].…”

Section: Small Molecule Inhibitors Of Metal Transport Proteinsmentioning

confidence: 99%

Developing drugs targeting transition metal homeostasis

Weekley

2017

Current Opinion in Chemical Biology

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Metal dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. Metal chelators and ionophores are well known modulators of transition metal homeostasis, and a number of these molecules are in clinical trials. Metalbinding compounds are not the only drugs capable of targeting transition metal homeostasis. This review presents recent highlights in the development of chelators and ionophores for the treatment of cancer and neurodegenerative disease. Moreover, we discuss the development of small molecules that alter copper and iron homeostasis by inhibiting metal transport proteins. Finally, we consider the emergence of metal regulatory factor 1 as a drug target in diseases where it mediates zinc-induced signalling cascades leading to pathogenesis.

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“…FAC or ferric nitrilotriacetate (Fe-NTA)) resulting in iron loading (7,44). In fact, their efficiency in incorporating NTBI is enhanced by the expression of DMT1A-I on the plasma membrane (45). It is notable that the expression level of endogenous FPN1 in HEp-2 cells was below the limit of detection of immunoblotting (Fig.…”

Section: Pcbp2 Directly Transfers Iron To Fpn1mentioning

confidence: 99%

Iron Export through the Transporter Ferroportin 1 Is Modulated by the Iron Chaperone PCBP2

Izumi

Richardson

Imada

et al. 2016

Journal of Biological Chemistry

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123

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Ferroportin 1 (FPN1) is an iron export protein found in mammals. FPN1 is important for the export of iron across the basolateral membrane of absorptive enterocytes and across the plasma membrane of macrophages. The expression of FPN1 is regulated by hepcidin, which binds to FPN1 and then induces its degradation. Previously, we demonstrated that divalent metal transporter 1 (DMT1) interacts with the intracellular iron chaperone protein poly(rC)-binding protein 2 (PCBP2). Subsequently, PCBP2 receives iron from DMT1 and then disengages from the transporter. In this study, we investigated the function of PCBP2 in iron export. Mammalian genomes encode four PCBPs (i.e. PCBP1-4). Here, for the first time, we demonstrated using both yeast and mammalian cells that PCBP2, but not PCBP1, PCBP3, or PCBP4, binds with FPN1. Importantly, ironloaded, but not iron-depleted, PCBP2 interacts with FPN1. The PCBP2-binding domain of FPN1 was identified in its C-terminal cytoplasmic region. The silencing of PCBP2 expression suppressed FPN1-dependent iron export from cells. These results suggest that FPN1 exports iron received from the iron chaperone PCBP2. Therefore, it was found that PCBP2 modulates cellular iron export, which is an important physiological process.Iron is an essential but potentially hazardous bio-metal (1). Because of its ability to readily accept or donate electrons, iron is a valuable cofactor that is used in oxygen transport, electron transfer, and DNA synthesis (2, 3). However, iron is potentially toxic because it catalyzes the generation of reactive oxygen species. The ensuing oxidative stress is associated with damage to cellular molecules, injury to tissues, and disease via processes including hydroxyl radical formation, glutathione depletion, protein aggregation, lipid peroxidation, and nucleic acid modification (4, 5).Despite its high abundance in nature, ferric iron is poorly bioavailable due to its exceedingly low solubility at physiological pH. Thus, the acquisition and usage of iron presents a considerable challenge to cells and organisms, which have evolved sophisticated mechanisms to satisfy their metabolic needs and concomitantly minimize the risk of toxicity.It has long been known that there is very little, yet potentially toxic, low-molecular-weight iron in rapidly metabolizing cells (6). However, the molecular mechanisms involved in intracellular iron transport have remained elusive (7). Recently, it was revealed that one of the mechanisms of iron transport and metabolism involves intracellular chaperone proteins (8). It was reported that poly(rC)-binding protein 1 (PCBP1), 3 also referred to as ␣-CP1 or hnRNP E1, is a cytosolic iron chaperone protein that delivers iron to ferritin (9). PCBP1 binds to iron with micromolar affinity at a molar ratio of 3:1 Fe:PCBP1. Notably, PCBP1 has been shown previously to function as an RNAand DNA-binding protein and has been identified as a member of a family of four homologous proteins containing three heterogeneous nuclear ribonucleoprotein K-homology (KH) do...

show abstract

Inhibition of iron uptake by ferristatin II is exerted through internalization of DMT1 at the plasma membrane

Cited by 14 publications

References 33 publications

Targeting iron metabolism in drug discovery and delivery

Targeting iron metabolism in drug discovery and delivery

Developing drugs targeting transition metal homeostasis

Iron Export through the Transporter Ferroportin 1 Is Modulated by the Iron Chaperone PCBP2

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