Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth

Deng, Zhiyong; Manz, David H.; Torti, Suzy V.; Torti, Frank M.

doi:10.18632/oncotarget.19288

Cited by 49 publications

(44 citation statements)

References 47 publications

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“…In hepatocellular carcinoma (HCC), IRP1 expression was lower in tumor than normal adjacent tissues, correlated the tumor stage and predicted overall and recurrence-free survival (78). In prostate cancer cells IRP2 was consistently overexpressed and knockdown inhibited growth in vitro and in vivo, while IRP1 was detected in some cell lines and knockdown only modestly reduced proliferation in vitro (77). IRP2 was overexpressed in colon cancer tissues compared to normal and interestingly, correlated with BRAF mutations and it was confirmed in vitro that IRP2 overexpression was driven by hyperactivation of the MAPK pathway (79).…”

Section: Iron Regulatory Proteinsmentioning

confidence: 82%

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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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Section: Iron Regulatory Proteinsmentioning

confidence: 82%

“…Cell lines Increased in some prostate and breast cancer cells (76,77). cells within the tumor microenvironment is important for progression.…”

Section: Iron Regulatory Protein-1 (Irp1)mentioning

confidence: 99%

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

et al. 2020

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“…By virtue of this mechanism, iron export is turned off when intracellular iron is already scarce. The IRP/IRE system appears to be relevant for tumor cell proliferation, too, in that activation of IRP2 along with an increase in iron content is documented for prostate cancer cells in vitro ( 54 ). Unexpectedly, overexpression of IRP1 impairs the growth of lung cancer cells transplanted into nude mice despite increased TFR1 levels ( 55 ).…”

Section: Ferroportin-1 Forms the “Iron Gate” To The Circulationmentioning

confidence: 99%

Iron in the Tumor Microenvironment—Connecting the Dots

et al. 2018

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Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.

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“…Several studies have suggested that IRP2 has an oncogenic activity. For example, IRP2 was found to promote breast and prostate cancer cell growth . In addition, IRP2 was found to be over‐expressed in several types of cancer including liver and lung .…”

Section: Discussionmentioning

confidence: 99%

“…For example, IRP2 was found to promote breast and prostate cancer cell growth. [33][34][35] In addition, IRP2 was found to be over-expressed in several types of cancer including liver and lung. 36,37 However, the signaling pathway mediated by IRP2 to promote tumorigenesis was not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Mdm2 is a target and mediator of IRP2 in cell growth control

et al. 2019

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Iron is an essential element to all living organisms and plays a vital role in many cellular processes, such as DNA synthesis and energy production. The Mdm2 oncogene is an E3 ligase and known to promote tumor growth. However, the role of Mdm2 in iron homeostasis is not certain. Here, we showed that Mdm2 expression was increased by iron depletion but decreased by iron repletion. We also showed that Iron Regulatory Protein 2 (IRP2) mediated iron‐regulated Mdm2 expression. Specifically, Mdm2 expression was increased by ectopic IRP2 but decreased by knockdown or knockout of IRP2 in human cancer cells as well as in mouse embryonic fibroblasts. In addition, we showed that IRP2‐regulated Mdm2 expression was independent of tumor suppressor p53. Mechanistically, we found that IRP2 stabilized Mdm2 transcript via binding to an iron response element (IRE) in the 3ʹUTR of Mdm2 mRNA. Finally, we showed that Mdm2 is required for IRP2‐mediated cell proliferation and Mdm2 expression is highly associated with IRP2 in both the normal and cancerous liver tissues. Together, we uncover a novel regulation of Mdm2 by IRP2 via mRNA stability and that the IRP2‐Mdm2 axis may play a critical role in cell growth.

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Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth

Cited by 49 publications

References 47 publications

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

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

Iron in the Tumor Microenvironment—Connecting the Dots

Mdm2 is a target and mediator of IRP2 in cell growth control

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