Research Papers:

Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1α

David Wetherell _, Graham S. Baldwin, Arthur Shulkes, Damien Bolton, Joseph Ischia, Oneel Patel

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Oncotarget. 2018; 9:8463-8477. https://doi.org/10.18632/oncotarget.23893

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David Wetherell1,2, Graham S. Baldwin1, Arthur Shulkes1, Damien Bolton1,2, Joseph Ischia1,2 and Oneel Patel1

1Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia

2Department of Urology, Austin Health, Heidelberg, Victoria, 3084, Australia

Correspondence to:

Oneel Patel, email: patelo@unimelb.edu.au

Keywords: castrate resistant; hypoxia inducible factor 1 alpha; prostate cancer; zinc; iron

Received: September 07, 2017     Accepted: November 14, 2017     Published: January 03, 2018


Zinc ions (Zn2+) are known to influence cell survival and proliferation. However the homeostatic regulation of Zn2+ and their role in prostate cancer (PC) progression is poorly understood. Therefore the subcellular distribution and uptake of Zn2+ in PC cells were investigated. Inductively coupled plasma mass spectroscopy and fluorescent microscopy with the Zn2+-specific fluorescent probe FluoZin-3 were used to quantify total and free Zn2+, respectively, in the normal prostate epithelial cell line (PNT1A) and three human PC cell lines (PC3, DU145 and LNCaP). The effects of Zn2+ treatment on proliferation and survival were measured in vitro using MTT assays and in vivo using mouse xenografts. The ability of Zn2+ to protect against oxidative stress via a HIF1α-dependent mechanism was investigated using a HIF1α knock-down PC3 model. Our results demonstrate that the total Zn2+ concentration in normal PNT1A and PC cells is similar, but PC3 cells contain significantly higher free Zn2+ than PNT1A cells (p < 0.01). PNT1A cells can survive better in the presence of high concentrations of Zn2+ than PC3 cells. Exposure to 10 μM Zn2+ over 72 hours significantly reduces PC3 cell proliferation in vitro but not in vivo. Zn2+ increases PC3 cell survival up to 2.3-fold under oxidative stress, and this protective effect is not seen in PNT1A cells or in a HIF1α-KD PC3 cell model. A state of Zn2+ dyshomeostasis exists in PC. HIF1α is an integral component of a Zn2+-dependent protective mechanism present in PC3 cells. This pathway may be clinically significant through its contribution to castrate-resistant PC survival.

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