Article

Increased level of exogenous zinc induces cytotoxicity and up-regulates the expression of the ZnT-1 zinc transporter gene in pancreatic cancer cells.

Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
The Journal of nutritional biochemistry (Impact Factor: 4.29). 04/2010; 22(1):79-88. DOI: 10.1016/j.jnutbio.2009.12.001
Source: PubMed

ABSTRACT A balance between zinc uptake by ZIP (SLC39) and efflux of zinc from the cytoplasm into subcellular organelles and out of the cell by ZnT (SLC30) transporters is crucial for zinc homeostasis. It is not clear whether normal and cancerous pancreatic cells respond differently to increased extracellular zinc concentrations. Use of flow cytometry-based methods revealed that treatment with as little as 0.01 mM zinc induced significant cytotoxicity in two human ductal adenocarcinoma cell lines. In contrast, normal human pancreatic islet cells tolerated as high as 0.5 mM zinc. Insulinoma cell lines of mouse and rat origin also succumbed to high concentrations of zinc. Exposure to elevated zinc concentrations enhanced the numbers of carcinoma but not primary islet cells staining with the cell-permeable zinc-specific fluorescent dye, FluoZin-3, indicating increased zinc influx in transformed cells. Mitochondrial membrane depolarization, superoxide generation, decreased antioxidant thiols, intracellular acidosis and activation of intracellular caspases characterized zinc-induced carcinoma cell death. Only the antioxidant glutathione but not inhibitors of enzymes implicated in apoptosis or necrosis prevented zinc-induced cytotoxicity in insulinoma cells. Immunoblotting revealed that zinc treatment increased the ubiquitination of proteins in cancer cells. Importantly, zinc treatment up-regulated the expression of ZnT-1 gene in a rat insulinoma cell line and in two human ductal adenocarcinoma cell lines. These results indicate that the exposure of pancreatic cancer cells to elevated extracellular zinc concentrations can lead to cytotoxic cell death characterized by increased protein ubiquitination and up-regulation of the zinc transporter ZnT-1 gene expression.

0 Bookmarks
 · 
93 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The redox-inert transition metal Zn is a micronutrient that plays essential roles in protein structure, catalysis and regulation of function. Inhalational exposure to ZnO or to soluble Zn salts in occupational and environmental settings leads to adverse health effects, the severity of which appears dependent on the flux of Zn(2+) presented to the airway and alveolar cells. The cellular toxicity of exogenous Zn(2+) exposure is characterized by cellular responses that include mitochondrial dysfunction, elevated production of reactive oxygen species and loss of signaling quiescence leading to cell death and increased expression of adaptive and inflammatory genes. Central to the molecular effects of Zn(2+) are its interactions with cysteinyl thiols, which alters their functionality by modulating their reactivity and participation in redox reactions. Ongoing studies aimed at elucidating the molecular toxicology of Zn(2+) in the lung are contributing valuable information about its role in redox biology and cellular homeostasis in normal and pathophysiology.
    Free Radical Biology & Medicine 06/2013; · 5.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dysfunctional zinc signaling is implicated in disease processes including cardiovascular disease, Alzheimer's disease and diabetes. Of the twenty-four mammalian zinc transporters, ZIP7 has been identified as an important mediator of the 'zinc wave' and in cellular signaling. Utilizing siRNA targeting Zip7 mRNA we have identified that Zip7 regulates glucose metabolism in skeletal muscle cells. An siRNA targeting Zip7 mRNA down regulated Zip7 mRNA 4.6-fold (p = 0.0006) when compared to a scramble control. This was concomitant with a reduction in the expression of genes involved in glucose metabolism including Agl, Dlst, Galm, Gbe1, Idh3g, Pck2, Pgam2, Pgm2, Phkb, Pygm, Tpi1, Gusb and Glut4. Glut4 protein expression was also reduced and insulin-stimulated glycogen synthesis was decreased. This was associated with a reduction in the mRNA expression of Insr, Irs1 and Irs2, and the phosphorylation of Akt. These studies provide a novel role for Zip7 in glucose metabolism in skeletal muscle and highlight the importance of this transporter in contributing to glycaemic control in this tissue.
    PLoS ONE 01/2013; 8(11):e79316. · 3.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer (adenocarcinoma) remains a deadly untreatable cancer with no effective early detection procedure. Little is known concerning the factors involved in the development of pancreatic malignancy, which impedes advancements in its treatment and detection. Altered cellular zinc has been implicated in several cancers. Recent studies provide evidence that zinc and zinc transporters are important factors in pancreatic cancer. This review discusses the current information relating to the status of zinc and zinc transporters in human pancreatic adenocarcinoma. Relationships of the physiology and biochemistry of zinc in mammalian cells are presented, which should be applied to the conduct, interpretation, and translational application of human studies and experimental models. Evidence from human pancreatic tissue studies supports a new concept of the role of zinc in the development of pancreatic adenocarcinoma. The zinc level of the normal ductal and acinar epithelium is markedly decreased in the development of the malignant cells and the premalignant PanIN cells. ZIP3 is identified as the likely zinc uptake transporter, which is down regulated concurrently with the loss of zinc. Ras responsive binding protein (RREB1) is identified as the possible transcription factor involved in the silencing of ZIP3 expression. The evidence supports the current views of transdifferentiation of PanIN epithelium to ductal adenocarcinoma, and the possibility that acinar epithelial dedifferentiation might be a source of premalignant cells. These zinc-associated events occur early in oncogenesis to protect the malignant cells from the cytotoxic effects of zinc levels that exist in the normal cells. Hopefully, this presentation will stimulate interest in and support for much needed research into the implications of zinc and zinc transporters as important events in pancreatic carcinogenesis. The potential exists for the RREB1-ZIP3-zinc concept and/or other implications of zinc as new approaches for the development of effective treatment and for diagnostic biomarkers for pancreatic cancer.
    Pancreatic disorders & therapy. 01/2013; Suppl 4.

Full-text (2 Sources)

View
143 Downloads
Available from
May 20, 2014