Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth
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Zhiyong Deng1, David H. Manz1,2, Suzy V. Torti1 and Frank M. Torti3
1Department of Molecular Biology and Biophysics, UCONN Health, Farmington, Connecticut 06032, USA
2School of Dental Medicine, UCONN Health, Farmington, Connecticut 06032, USA
3Department of Medicine, UCONN Health, Farmington, Connecticut 06032, USA
Suzy V. Torti, email: [email protected]
Keywords: prostate cancer, iron, iron-responsive element-binding protein, cell cycle, apoptosis
Received: April 19, 2017 Accepted: June 03, 2017 Published: July 17, 2017
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.
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