Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/17862
Title: Zinc ion dyshomeostasis increases resistance of prostate cancer cells to oxidative stress via upregulation of HIF1α.
Authors: Wetherell, David;Baldwin, Graham S;Shulkes, Arthur;Bolton, Damien M;Ischia, Joseph J;Patel, Oneel
Affiliation: Department of Urology, Austin Health, Heidelberg, Victoria, Australia
Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 3-Jan-2018
EDate: 2018-02-02
Citation: Oncotarget 2018; 9(9): 8463-8477
Abstract: 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/17862
DOI: 10.18632/oncotarget.23893
ORCID: 0000-0001-5783-3642
0000-0002-0944-8747
0000-0002-5145-6783
PubMed URL: 29492208
Type: Journal Article
Subjects: castrate resistant
hypoxia inducible factor 1 alpha
iron
prostate cancer
zinc
Appears in Collections:Journal articles

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