DMT1 and iron transport

Izumi, Yasukatsu; Kishi, Fumio

doi:10.1016/j.freeradbiomed.2018.07.020

Cited by 216 publications

(126 citation statements)

References 84 publications

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“…Interestingly, we found also an increase of M1 markers, suggesting that Mifamurtide is able to induce a M1/M2 intermediate macrophage phenotype and that macrophage activation state is still ready to promptly cooperate with the immune system. Mifamurtide also modulates the delicate balance of iron, in fact Mifamurtide-activated macrophages show an increase of DMT1, an important iron-uptake transporter [37] and an enhanced iron release. This interesting result suggests that the iron sequestration in the reticuloendothelial system may be actively and efficiently counteracted by the induced iron release, according to an anti-inflammatory profile of the drug.…”

Section: Discussionmentioning

confidence: 99%

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

et al. 2020

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Tumor-associated macrophages and their alternative activation states together with cytokines and growth factors trapped in tumor microenvironment contribute to the progression of OS. In contrast to other tumor types, M2 polarized macrophages, reduce metastasis and improve survival in osteosarcoma patients. Mifamurtide is an immunomodulatory drug given together with standard adjuvant chemotherapy in high-grade osteosarcoma to improve outcome. Macrophages obtained from peripheral blood mononucleated cells of healthy donors and MG63 cells were cultured alone and together, and treated with Mifamurtide. We analyzed the effects of Mifamurtide on macrophage polarization and on MG63 proliferation, migration and differentiation, evaluating the expression of M1/M2 and osteoblast markers and molecules involved in metastasis and proliferation pathways. Our data suggest that Mifamurtide, switching macrophage polarization towards a TAM-like intermediate M1/M2 phenotype, may modulate the delicate balance between pro-inflammatory and immunomodulatory macrophage functions. Moreover, Mifamurtide may inhibit the cellular proliferation and induce the tumor cell differentiation, probably through the down regulation of pSTAT3, pAKT and IL-17R.

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Section: Discussionmentioning

confidence: 99%

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

et al. 2020

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“…Most iron is stored in red blood cells and is a major source of systemic iron through their degradation, releasing iron from heme and making it available for other cells to utilize (5). Dietary iron uptake occurs through divalent metal ion transporter 1 (DMT1) expressed on enterocytes in the duodenum and upper ilium in the small intestine (6). Iron is transported from the sites of absorption to other tissues predominantly by binding to the protein transferrin (Tf).…”

Section: Cellular Iron Metabolismmentioning

confidence: 99%

“…For example, agents which reduce intracellular iron (e.g., membrane-permeable iron chelators) induce proteasomal degradation of ferritin, whilst those that limit iron uptake (e.g., impermeable iron chelators) promote degradation via the lysosome and activate autophagy (27). Iron import is also controlled by lysosomal or proteasomal degradation of TfR1 and DMT1 or by release from the plasma membrane into extracellular vesicles or endosomes (6,30,31). Therefore, posttranslational mechanisms are another level of control to ensure iron homeostasis.…”

Section: Iron Homeostasismentioning

confidence: 99%

“…Three membrane iron transporters have been identified DMT1, Zrt-, and Irt-like protein 14 (ZIP14) and zinc transporter ZIP8 (ZIP8). DMT1 is important for iron uptake across the apical membrane of the gastrointestinal tract and intracellular endosomal membrane transport (6). Several reports suggest DMT1 is responsible for intracellular iron accumulation to support CRC proliferation (104)(105)(106).…”

Section: Iron Uptakementioning

confidence: 99%

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Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

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“…The transferrin system was established during the 1970 and 1980s, 21 but it was in the late 1990s that iron transporters started to be cloned 22 . In mammals, iron is absorbed through the gastrointestinal system, specifically by duodenal mucosal cells with DMT1 (SLC11A2) 23 . Iron solubility is significantly increased by acidic mucus of the stomach immediately prior to the duodenum, where it is thereafter neutralized with bile and pancreatic juice at its second portion.…”

Section: Iron Metabolismmentioning

confidence: 99%

Ferroptosis at the crossroads of infection, aging and cancer

et al. 2020

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Despite significant developments and persistent efforts by scientists, cancer is one of the primary causes of human death worldwide. No form of life on Earth can survive without iron, although some species can live without oxygen. Iron presents a double‐edged sword. Excess iron is a risk for carcinogenesis, while its deficiency causes anemia, leading to oxygen shortage. Every cell is eventually destined to death, either through apoptosis or necrosis. Regulated necrosis is recognized in distinct forms. Ferroptosis is defined as catalytic Fe(II)‐dependent regulated necrosis accompanied by lipid peroxidation. The main observation was necrosis of fibrosarcoma cells through inhibition of cystine/glutamate antiporter with erastin, which reduced intracellular cysteine and, thus, glutathione levels. Our current understanding of ferroptosis is relative abundance of iron (catalytic Fe[II]) in comparison with sulfur (sulfhydryls). Thus, either excess iron or sulfur deficiency causes ferroptosis. Cell proliferation inevitably requires iron for DNA synthesis and energy production. Carcinogenesis is a process toward iron addiction with ferroptosis resistance. Conversely, ferroptosis is associated with aging and neurodegeneration. Ferroptosis of immune cells during infection is advantageous for infectious agents, whereas ferroptosis resistance incubates carcinogenic soil as excess iron. Cancer cells are rich in catalytic Fe(II). Directing established cancer cells to ferroptosis is a novel strategy for discovering cancer therapies. Appropriate iron regulation could be a tactic to reduce and delay carcinogenesis.

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DMT1 and iron transport

Cited by 216 publications

References 84 publications

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Ferroptosis at the crossroads of infection, aging and cancer

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