Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-κB-dependent pathway

Department of Urological Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
The Prostate (Impact Factor: 3.57). 09/2008; 68(13):1443-9. DOI: 10.1002/pros.20810
Source: PubMed


Zinc accumulation diminishes early in the course of prostate malignancy and continues to decline during progression toward hormone-independent growth. In contrast, constitutive levels of NF-kappaB activity increase during progression of prostate cells toward greater tumorigenic potential. We have reported previously that physiological levels of zinc suppress NF-kappaB activity in prostate cancer cells and reduce expression of pro-angiogenic and pro-metastatic cytokines VEGF, IL-6, IL-8, and MMP-9 associated with negative prognostic features in prostate cancer.
Intracellular zinc levels were examined by atomic absorption spectroscopy. NF-kappaB activity was examined by TransAm and Luciferase reporter assays, and Western blot analysis of p50 nuclear translocation. VEGF, IL-6 and IL-8 levels were assessed by ELISA.
Selective zinc deficiency induced by the membrane-permeable zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) increases activation of NF-kappaB and up-regulates expression of the NF-kappaB controlled pro-angiogenic and pro-metastatic cytokines VEGF, IL-6 and IL-8 in androgen-independent PC-3 and DU-145 prostate cancer cells. Pre-incubation with I kappaB alpha dominant mutant adenovirus efficiently blocks expression of these cytokines in zinc deficient cells indicating that the observed effects are NF-kappaB dependent.
Our findings suggest that zinc deficiency may contribute to the tumor progression via augmented expression of the NF-kappaB-dependent pro-tumorigenic cytokines.

Download full-text


Available from: Peter Makhov,
  • Source
    • "Zn (K d : 2.6 × 10 −16 M), but it can also chelate Fe (K d : 2.5 × 10 −15 M) and Cu (K d : 3.0 × 10 −20 M) with similar or higher avidity (Golovine et al., 2008 "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Developmental zinc (Zn) deficiency increases the incidence of heart anomalies in rat fetuses, in regions and structures derived from the outflow tract. Given that the development of the outflow tract requires the presence of cardiac neural crest cells (cNCC), we speculated that Zn deficiency selectively kills cNCC and could lead to heart malformations.METHODS Cardiac NCC were isolated from E10.5 rat embryos and cultured in control media (CTRL), media containing 3 μM of the cell permeable metal chelator N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylene diamine (TPEN), or in TPEN-treated media supplemented with 3 μM Zn (TPEN + Zn). Cardiac NCC were collected after 6, 8, and 24 h of treatment to assess cell viability, proliferation, and apoptosis.RESULTSThe addition of TPEN to the culture media reduced free intracellular Zn pools and cell viability as assessed by low ATP production, compared to cells grown in control or Zn-supplemented media. There was an accumulation of reactive oxygen species, a release of mitochondrial cytochrome c into the cytoplasm, and an increased cellular expression of active caspase-3 in TPEN-treated cNCC compared to cNCC cultured in CTRL or TPEN + Zn media.CONCLUSION Zn deficiency can result in oxidative stress in cNCC, and subsequent decreases in their population and metabolic activity. These data support the concept that Zn deficiency associated developmental heart defects may arise in part as a consequence of altered cNCC metabolism
    Birth Defects Research Part B Developmental and Reproductive Toxicology 02/2015; 104(1). DOI:10.1002/bdrb.21135 · 0.77 Impact Factor
  • Source
    • "The mechanism by which zinc may affect the adaptive and innate immunity is by targeting NF-kB, a transcriptional regulatory factor of proinflammatory responses (Hayden and Ghosh, 2008). In dietary zinc deficiency, in ageing or in depletion of intracellular zinc with a zinc-specific chelator, NFkB activation increases with subsequent proinflammatory cytokine gene expressions and production leading to the appearance of chronic inflammation coupled with some age-related degenerative diseases (Bao et al., 2010; Golovine et al., 2008; Mocchegiani et al., 2013b). In humans, zinc supplementation improves the immune functions and decreases the inflammation (Mocchegiani et al., 2013b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients' absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient-gene interactions in ageing and their impact on the healthy state with a focus on the method of protein-metal speciation analysis. The association between micronutrient-gene interactions and the protein-metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.
    Mechanisms of ageing and development 01/2014; 136-137. DOI:10.1016/j.mad.2013.12.007 · 3.40 Impact Factor
  • Source
    • "Similarly, increased ZIP4 expression in pancreatic cells is associated with pancreatic cancer (Li et al., 2007, 2009; Zhang et al., 2010, 2011). In contrast, decreased zinc accumulation is associated with progression of prostate cancer (Huang et al., 2006; Golovine et al., 2008b; Johnson et al., 2010). Reduced accumulation of zinc in tumorigenic prostate epithelial cells might be due to decreased expression of ZIP1 protein or redistribution of ZIP3 to lysosomal vesicles (Huang et al., 2006; Johnson et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Zinc is a trace element nutrient that is essential for life. This mineral serves as a cofactor for enzymes that are involved in critical biochemical processes and it plays many structural roles as well. At the cellular level, zinc is tightly regulated and disruption of zinc homeo-stasis results in serious physiological or pathological issues. Despite the high demand for zinc in cells, free or labile zinc must be kept at very low levels. In humans, two major zinc transporter families, the SLC30 (ZnT) family and SLC39 (ZIP) family control cellular zinc homeostasis. This review will focus on the SLC39 transporters. SLC39 transporters primar-ily serve to pass zinc into the cytoplasm, and play critical roles in maintaining cellular zinc homeostasis. These proteins are also significant at the organismal level, and studies are revealing their link to human diseases. Therefore, we will discuss the function, structure, physiology, and pathology of SLC39 transporters.
Show more