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Review
. 2018 Nov 27:8:547.
doi: 10.3389/fonc.2018.00547. eCollection 2018.

Iron Metabolism in Prostate Cancer; From Basic Science to New Therapeutic Strategies

Driton Vela  1
Affiliations
Review

Iron Metabolism in Prostate Cancer; From Basic Science to New Therapeutic Strategies

Driton Vela. Front Oncol. .

Abstract

An increasing amount of research has recently strengthened the case for the existence of iron dysmetabolism in prostate cancer. It is characterized with a wide array of differential expression of iron-related proteins compared to normal cells. These proteins control iron entry, cellular iron distribution but also iron exit from prostate cells. Iron dysmetabolism is not an exclusive feature of prostate cancer cells, but it is observed in other cells of the tumor microenvironment. Disrupting the machinery that secures iron for prostate cancer cells can retard tumor growth and its invasive potential. This review unveils the current understanding of the ways that prostate cancer cells secure iron in the tumor milieu and how can we exploit this knowledge for therapeutic purposes.

Keywords: cancer stem cells; ferroportin; hepcidin; iron metabolism; iron responsive element-binding protein 2; prostate cancer; transferrin receptor 1; tumor associated macrophages.

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Figures

Figure 1
Figure 1
Iron metabolism in prostate cancer microenvironment. Prostate cancer cells are characterized with a differential expression of iron-related proteins compared to normal cells. These changes include upregulation of iron-import proteins (TFR1), overexpression of intracellular regulators of iron metabolism (IRP2), downregulation of iron export (FPN). In addition, recent data suggest that prostate cancer cells increase their labile iron pool by increasing the activity of hydrogen pumps and ferrireductases, which causes increased release of iron from endosomes. These actions will further increase labile iron pool. In addition, prostate cancer cells interact with their surroundings to increase iron delivery. This is believed to be done by stimulating TAMs to produce Lp2, which then binds iron and delivers it to cancer cells. Also, PCa cells secrete hepcidin locally to reduce their iron export through FPN downregulation and Lp2 to increase iron supply. Iron dymetabolism is also a feature of CSCs and sensescent prostate cells, whose numbers are increased in cancer. It is believed that iron dysregulation observed in CSCs is important for their survival and renewal of cancer cells. On the other hand, senescent prostate cells are known to secrete different molecules, some of which can directly influence the production of iron-related proteins by prostate cancer cells. CSC, cancer stem cell; Feph, ferritinophagy; FPN, ferroportin; Hepc, hepcidin; IL-6, interleukin-6; IRP, iron responsive element-binding protein; LIP, labile iron pool; Lp2R, lipocalin 2 receptor; SASP, senescence-associated secretory phenotype; STAMP2, six transmembrane prostate protein 2; TAM, tumor-associated macrophage; TFR1, transferrin receptor 1; V-ATPase, vacuolar ATPase; Wnt, wingless/integrated pathway.
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