Konstantin Salnikow - Academia.edu (original) (raw)

Papers by Konstantin Salnikow

Cancer Research, Jan 15, 2009

Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic ... more Activation of hypoxia-inducible factors (HIF), responsible for tumor angiogenesis and glycolytic switch, is regulated by reduced oxygen availability. Normally, HIF-A 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-A hydroxylating enzyme PHD2. The interaction was confirmed by a pull-down assay, coimmunoprecipitation, and colocalization in both normoxic and hypoxic conditions. Furthermore, MAGE-9, the closest homologue of MAGE-11, was also found to interact with PHD2. MAGE-11 inhibited PHD activity without affecting protein levels. This inhibition was accompanied by stabilization of ectopic or endogenous HIF-1A protein. Knockdown of MAGE-11 by small interfering RNA results in decreased hypoxic induction of HIF-1A and its target genes. Inhibition of PHD by MAGE-11, and following activation of HIFs, is a novel tumor-associated HIF regulatory mechanism. This finding provides new insights into the significance of MAGE expression in tumors and may provide valuable tools for therapeutic intervention because of the restricted expression of the MAGE gene family in cancers, but not in normal tissues.

Supplementary Figure 2 from Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydr... more Supplementary Figure 2 from Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response

All in-text references underlined in blue are linked to publications on ResearchGate, letting you... more All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.

Nickel and Its Surprising Impact in Nature

... 595 6.1.2. Extracellular Matrix and Transcription 598 6.2. ATF-1 599 Metal Ions in Life Scien... more ... 595 6.1.2. Extracellular Matrix and Transcription 598 6.2. ATF-1 599 Metal Ions in Life Sciences, Volume 2 Edited by Astrid Sigel, Helmut Sigel and Roland KO Sigel © 2007 John Wiley & Sons, Ltd. ISBN: 0-470-01671-X Page 2. 582 SALNIKOW and KASPRZAK Met. ...

Toxicology and Applied Pharmacology, 2004

Exposure to ambient air particulate matter (PM) is associated with increased mortality and morbid... more 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. One type of PM, residual oil fly ash (ROFA), is of particular interest. ROFA does not contain much organic material, but does contain relatively high quantities of transition metals, predominantly nickel, vanadium, and iron, as well as black carbon and sulfates. In this study, we investigated the effect of two metals (iron and nickel) on the induction of ''hypoxia-like'' stress and the production of interleukins (ILs) in minimally transformed human airway epithelial cells (1HAEo À). We found that exposure to soluble nickel sulfate results in the induction of hypoxia-inducible genes and IL-8 production by the 1HAEo À cells. The simultaneous addition of iron in either ferric or ferrous form and nickel completely inhibited IL-8 production and had no effect on ''hypoxia-like'' stress caused by nickel, suggesting the existence of two different pathways for the induction ''hypoxia-like'' stress and IL-8 production. The effect of nickel was not related to the blocking of iron entry into cells since the level of intracellular iron was not affected by co-exposure with nickel. The obtained data indicate that nickel can induce different signaling pathways with or without interference with iron metabolism. Our observations suggest that in some cases the excess of iron in PM can cancel the effects of nickel.

Journal of Toxicology and Environmental Health, Part A, 2006

It was hypothesized that relative mass relationships among select constituent metals and iron (Fe... more 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. However, AM IRP activity can be affected by an increased presence of nitric oxide generated by inducible nitric oxide synthase (iNOS). This study sought to determine if any changes in AM IRP activity induced by PM(2.5) constituents V, Mn, or Al were independent from effects of the metals on cell NO formation. NR8383 rat AM were exposed to Fe3+ alone or combined with V, Mn, or Al at metal:Fe ratios representative of those in PM(2.5) collected in New York City, Los Angeles, and Seattle during fall 2001. Cells were then assessed for changes in IRP activity and iNOS expression. Phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2 levels were also measured since activated ERKs are involved in signaling pathways that lead to increased iNOS expression. The results indicate that V and Al, and to a lesser extent Mn, altered IRP activity, though the effects were not consistently concentration dependent. Furthermore, while V and Mn treatments did not induce iNOS expression, Al did. These results confirmed our hypothesis that certain metals associated with PM(2.5) might alter the pulmonary immunocompetence of exposed hosts by affecting the Fe status of AM, a major class of deep lung defense cells.

Inhalation Toxicology, 2007

The extent of adverse health effects, including induction/exacerbation of infectious lung disease... more 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 PM2.5 from various sites, we hypothesized that select metals (e.g., V, Al, and Mn) in each PM2.5 caused changes in alveolar macrophage (AM) Fe status that, ultimately, would lead to altered antibacterial function. To test this, iron-response protein (IRP) binding activity in a rat AM cell line was assessed after exposure to Fe alone and in conjunction with V, Mn, and/or Al at ratios of V:Fe, Al:Fe, or Mn:Fe encountered in PM2.5 samples from New York City, Los Angeles, and Seattle. Results indicated that V and Al each significantly altered IRP activity, though effects were not consistently ratio-(i.e., dose-) dependent; Mn had little impact on activity. We conclude that the reductions in Fe status detected here via the IRP assay arose, in part, from effects on transferrin-mediated Fe3+ delivery to the AM. Ongoing studies using this assay are allowing us to better determine: (1) whether mass (and/or molar) relationships between Fe and V, Al, and/or Mn in any PM2.5 sample consistently govern the extent of change in AM Fe status; (2) how much any specified PM2.5 constituent (metal or nonmetal) contributes to the overall disruption of Fe status found induced by an intact parent sample; and (3) whether induced changes in binding activity are relatable to other changes expected to occur in the AM, that is, in IRP-dependent mRNA/levels of ferritin/transferrin receptor and Fe-dependent functions. These studies demonstrate that pollutant-induced effects on lung cell Fe status can be assessed in a reproducible manner using an assay that can be readily performed by investigators who might otherwise have no access to other very costly analytical equipment, such as graphite atomic absorption or x-ray fluorescence spectro(photo)meters.

Environmental Health Perspectives, 2005

Nickel compounds are known to cause respiratory cancer in humans and induce tumors in experimenta... more 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. Instead, we propose that it is formation of metal complexes with proteins and other molecules that changes cellular homeostasis and provides conditions for selection of cells with transformed phenotype. This is concordant with the major requirement for nickel carcinogenicity, which is prolonged action on the target tissue. If DNA is not the main nickel target, is there another unique molecule that can be attacked with carcinogenic consequences? Our recent observations indicate that ascorbate may be such a molecule. Nickel depletes intracellular ascorbate, which leads to the inhibition of cellular hydroxylases, manifested by the loss of hypoxia-inducible factor (HIF)-1α and-2α hydroxylation and hypoxia-like stress. Proline hydroxylation is crucial for collagen and extracellular matrix assembly as well as for assembly of other protein molecules that have collagen-like domains, including surfactants and complement. Thus, the depletion of ascorbate by chronic exposure to nickel could be deleterious for lung cells and may lead to lung cancer.

Chemical Research in Toxicology, 2008

Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to i... more 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. Toxic metals are capable of potent and surprisingly selective activation of stress-signaling pathways, which are known to contribute to the development of human cancers. Depending on the metal, ascorbate (vitamin C) has been found to act either as a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via both oxidative and nonoxidative (DNA adducts) mechanisms, metals can also cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies provided strong support for the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely to stem from their ability to interfere with DNA repair processes. Overall, metal carcinogenesis appears to require the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells. Contents 1. Introduction 28 2. Nickel 28 2.1. Human Exposure and Carcinogenicity 28 2.2. Genetic and Epigenetic Changes 29 2.3. Activation of Hypoxic Signaling 29 2.4. Ni(II) as a Cocarcinogen 31 3. Arsenic 31 3.1. Human Exposure and Carcinogenicity 31 3.2. Increased Cellular Proliferation 32 3.3. Apoptotic Effects of Arsenite Exposure and NF-kB Signaling Pathway 33 3.4. Genetic and Epigenetic Changes 33 3.5. Metabolic Changes 33 3.6. Arsenic as a Cocarcinogen 34 4. Chromium 34 4.1. Human Exposure and Carcinogenicity 34 4.2. Cr(VI) Metabolism and DNA Damage 35 4.

Cancer Biology & Therapy, 2004

Normal development and function of metazoan organisms depend on oxygen availability. The level of... more Normal development and function of metazoan organisms depend on oxygen availability. The level of oxygen can be sensed by individual cells, which respond to reduced oxygenation (hypoxia) largely through activation of hypoxia-inducible factor-1 (HIF-1). At the organism level the response to hypoxia involves an increase in red blood cell production. Within tissues, HIF activation increases the blood supply and blood vessel growth. At the individual cell level it is manifested as an increase in anaerobic metabolism in order to sustain basic cellular functions. Iron is central to the oxygen sensing mechanism, and sensitivity to other metals, namely cobalt and nickel, is a distinctive feature of the HIF system; in fact, this is often used as an initial way of implicating HIF-1 in a biological response. Historically, the fact that nickel or cobalt mimicked hypoxia provided an important clue as to the nature of the oxygen sensing mechanism. It also raises the possibility that nickel or cob...