Role of iron in cancer.

Iron is an essential metal for cellular metabolism. The reduced form of iron is a cofactor in numerous redox reactions in the cell and is therefore required for many vital physiological functions. Since iron is an oxidatively active metal, its homeostasis is tightly regulated in healthy cell.

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q.

Effects of ascorbic acid on carcinogenicity and acute toxicity of nickel subsulfide, and on tumor transplants growth in gulonolactone oxidase knock-out mice and wild-type C57BL mice.

The aim of this study was to test a hypothesis that ascorbate depletion could enhance carcinogenicity and acute toxicity of nickel. Homozygous L-gulono--lactone oxidase gene knock-out mice (Gulo-/- mice) unable to produce ascorbate and wild-type C57BL mice (WT mice) were injected intramuscularly with carcinogenic nickel subsulfide (Ni₃S₂), and observed for the development of injection site tumors for 57 weeks. Small pieces of one of the induced tumors were transplanted subcutaneously into separate groups of Gulo-/- and WT mice and the growth of these tumors was measured for up to 3 months.

Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response.

Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-alpha proteins are maintained at low levels, controlled by site-specific hydroxylation carried out by HIF prolyl hydroxylases (PHD) and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitin ligase. Using a yeast two-hybrid screen, we identified an interaction between melanoma antigen-11 (MAGE-11) cancer-testis antigen and the major HIF-alpha hydroxylating enzyme PHD2.

Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

The exposure of cells to several metal ions stabilizes HIF-1 alpha protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases.

Regulation of hypoxia-inducible genes by ETS1 transcription factor.

Hypoxia-inducible factor (HIF-1) regulates the expression of genes that facilitate tumor cell survival by making them more resistant to therapeutic intervention. Recent evidence suggests that the activation of other transcription factors, in cooperation with HIF-1 or acting alone, is involved in the upregulation of hypoxia-inducible genes. Here we report that high cell density, a condition that might mimic the physiologic situation in growing tumor and most probably representing nutritional starvation, upregulates hypoxia-inducible genes.

Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors.

Mutations in the VHL gene are associated with highly vascular tumors of kidney, brain, retina, and adrenal gland. The inability of the mutant VHL protein to destabilize HIF-1 plays a crucial role in malignant angiogenesis. VHL is also associated with ECM assembly but the molecular mechanisms of this activity remain unclear.

Extracellular matrix and HIF-1 signaling: the role of prolidase.

Hypoxia-inducible factor-1 (HIF-1) plays an important role in stress-responsive gene expression. Although primarily sensitive to hypoxia, HIF-1 signaling can be regulated by a number of stress factors including metabolic stress, growth factors and molecules present in the extracellular matrix (ECM). Degradation of ECM by metalloproteinases (MMP) is important for tumor progression, invasion and metastasis.

Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium.

Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to increase cancer incidence among affected individuals. Recent epidemiological studies have found that carcinogenic risks associated with chromate and iAs exposures were substantially higher than previously thought, which led to major revisions of the federal standards regulating ambient and drinking water levels. Genotoxic effects of Cr(VI) and iAs are strongly influenced by their intracellular metabolism, which creates several reactive intermediates and byproducts.

Detection of changes in alveolar macrophage iron status induced by select PM2.5-associated components using iron-response protein binding activity.

The extent of adverse health effects, including induction/exacerbation of infectious lung disease, arising from entrainment of equivalent amounts (or exposure to a fixed increment) of fine particulate matter (PM2.5) can vary from region to region or city to city in a region. To begin to explain how differing effects on host resistance might arise after exposure to PM2.

The role of ascorbate in the modulation of HIF-1alpha protein and HIF-dependent transcription by chromium(VI) and nickel(II).

Molecular oxygen is involved in hydroxylation and subsequent degradation of HIF-1alpha, a subunit of HIF-1 transcription factor; therefore oxygen shortage (hypoxia) stabilizes this protein. However, HIF-1alpha can also be stabilized by transition metal ions in the presence of oxygen, suggesting that a different mechanism is involved in metal-induced hypoxic stress. Recently, we showed that the depletion of intracellular ascorbate by metals may lead to the inhibition of hydroxylases.

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13.

DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression.

Effects of select PM-associated metals on alveolar macrophage phosphorylated ERK1 and -2 and iNOS expression during ongoing alteration in iron homeostasis.

It was hypothesized that relative mass relationships among select constituent metals and iron (Fe3+) govern the pulmonary immunotoxic potential of any PM(2.5) sample, as these determine the extent to which Fe3+ binding by transferrin is affected (resulting in altered alveolar macrophage [AM] Fe status and subsequent antibacterial function). Iron response protein (IRP) binding activity is a useful indirect measurement of changes in Fe status, as reductions in cell Fe levels lead to increases in IRP binding.

Quantum chemical modeling of reaction mechanism for 2-oxoglutarate dependent enzymes: effect of substitution of iron by nickel and cobalt.

Enzymatic hydroxylation reactions carried out by 2-oxoglutarate (2OG) dependent iron-containing oxygenases were recently implicated in oxygen sensing. In addition to oxygen depletion, two metals, cobalt and nickel, are capable of inducing hypoxic stress in cells by inhibiting oxygenase activity. Two possible scenarios have been proposed for the explanation of the hypoxic effects of cobalt and nickel: oxidation of enzyme-bound iron following cobalt or nickel exposure, and substitution of iron by cobalt or nickel.

Ascorbate depletion mediates up-regulation of hypoxia-associated proteins by cell density and nickel.

Exposure of human lung cells to carcinogenic nickel compounds in the presence of oxygen up-regulated carbonic anhydrase IX (CA IX) and NDRG1/Cap43, both known as intrinsic hypoxia markers and cancer-associated genes. This suggests that factors other than a shortage of oxygen may be involved in this induction. Both proteins can also be induced in the presence of oxygen by culturing these cells to a high density without medium change.

Microarray analysis of altered gene expression in murine fibroblasts transformed by nickel(II) to nickel(II)-resistant malignant phenotype.

B200 cells are Ni(II)-transformed mouse BALB/c-3T3 fibroblasts displaying a malignant phenotype and increased resistance to Ni(II) toxicity. In an attempt to find genes whose expression has been altered by the transformation, the Atlas Mouse Stress/Toxicology cDNA Expression Array (Clontech Laboratories, Inc., Palo Alto, CA) was used to analyze the levels of gene expression in both parental and Ni(II)-transformed cells.

Ascorbate depletion: a critical step in nickel carcinogenesis?

Nickel compounds are known to cause respiratory cancer in humans and induce tumors in experimental animals. The underlying molecular mechanisms may involve genotoxic effects; however, the data from different research groups are not easy to reconcile. Here, we challenge the common premise that direct genotoxic effects are central to nickel carcinogenesis and probably to that of other metals.

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain.

Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies.

Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress.

Exposure of cells to carcinogenic compounds of nickel(II) and cobalt(II) causes activation of the HIF-1 transcription factor and up-regulates a battery of hypoxia-inducible genes. However, the mechanism of HIF-1 activation by these metals is not known. It was shown recently that hydroxylation of prolines in the HIFalpha subunit of HIF-1 is required for its binding with the von Hippel-Lindau tumor suppressor protein and the subsequent proteasomal destruction.

Effect of nickel and iron co-exposure on human lung cells.

Exposure to ambient air particulate matter (PM) is associated with increased mortality and morbidity in susceptible populations. The epidemiological data also suggest a relationship between PM air pollution and impairment of cardiopulmonary function. The mechanisms that may be responsible for these effects are not fully understood and are likely related to perturbations of cellular and molecular functions.

Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas.

Nickel compounds are carcinogenic and induce malignant transformation of cultured cells. Since nickel has low mutagenic potential, it may act predominantly through epigenetic mechanisms, including down-regulation of tumor suppressor genes. FHIT is a tumor suppressor gene whose expression is frequently reduced or lost in tumors and pre-malignant lesions.

Altered N-myc downstream-regulated gene 1 protein expression in African-American compared with caucasian prostate cancer patients.

Purpose: The protein encoded by N-myc downstream-regulated gene 1 (NDRG1) is a recently discovered protein whose transcription is induced by androgens and hypoxia. We hypothesized that NDRG1 expression patterns might reveal a biological basis for the disparity of clinical outcome of prostate cancer patients with different ethnic backgrounds.

Experimental Design: Patients who underwent radical prostatectomy between 1990 and 2000 at Veterans Administration Medical Center of New York were examined.

Nickel-induced down-regulation of serpin by hypoxic signaling.

Nickel (Ni) carcinogenesis is thought to involve gene chip silencing by epigenetic mechanisms. Serpina3g, a member of the mouse serpin family, was among the most down-regulated genes (32-fold) in response to Ni exposure of mouse cells based on the Affymetrix gene chip. Serpina3g down-regulation was controlled by a hypoxia inducible factor (HIF) mechanism.