Abstract
Iron-responsive element-binding proteins (IRPs) are master regulators of cellular iron homeostasis. Our previous work demonstrated that iron homeostasis is altered in prostate cancer and contributes to prostate cancer progression. Here we report that prostate cancer cells overexpress IRP2 and that overexpression of IRP2 drives the altered iron phenotype of prostate cancer cells. IRP2 knockdown in prostate cancer cell lines reduces intracellular iron and causes cell cycle inhibition and apoptosis. Cell cycle analysis demonstrates that IRP2-depleted prostate cancer cells accumulate in G0/G1 due to induction of p15, p21, and p27. Activation of these pathways is sufficient to significantly reduce the growth of PC3 prostate tumors in vivo. In contrast, IRP1 knockdown does not affect iron homeostasis and only modestly affects cell growth, likely through an iron-independent mechanism. These results demonstrate that upregulation of IRP2 in prostate cancer cells co-opts normal iron regulatory mechanisms to facilitate iron retention and drive enhanced tumor growth.
Highlights
Iron is essential for normal cellular metabolism, growth, and replication
Iron-responsive element-binding proteins (IRPs)/iron responsive elements (IREs) binding in the 5’ untranslated regions (UTR) suppresses mRNA translation while IRP/IRE binding in the 3’ UTR stabilizes mRNA transcripts and results in increased translation. 5’ IREs are found in mRNAs encoding proteins involved in iron storage and export, such as ferritin and ferroportin (FPN), while 3’ IREs are found in mRNAs encoding proteins involved in iron import, such as transferrin receptor (TfR1) and divalent metal transporter 1 (DMT1)
Transferrin receptor 1 is increased and ferritin H is decreased in prostate cancer cells compared to normal prostate epithelia
Summary
Iron is essential for normal cellular metabolism, growth, and replication. Iron and iron-containing functional groups, such as heme and iron-sulfur clusters, are critical to the function of proteins involved in numerous cellular processes including mitochondrial respiration, DNA synthesis, and cell cycle regulation [1]. Cellular iron homeostasis is tightly controlled [3, 4]. Iron-responsive element-binding proteins (IRPs) are master regulators of cellular iron homeostasis. The two IRPs, IRP1 and IRP2, share 61% sequence identity [5]. Both IRPs post-transcriptionally regulate iron levels by binding to iron responsive elements (IREs), stem loop structures in the 5’ or 3’ untranslated regions (UTR) of selected mRNAs [6, 7]. IRP/IRE binding in the 5’ UTR suppresses mRNA translation while IRP/IRE binding in the 3’ UTR stabilizes mRNA transcripts and results in increased translation. IRP/IRE binding is normally stimulated in low iron conditions and orchestrates an increase in cellular iron [1]
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