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Proteomic Responses of BEAS-2B Cells to Nontoxic and Toxic Chromium: Protein Indicators of Cytotoxicity Conversion
Bruno, M., J. Ross, AND Y. Ge. Proteomic Responses of BEAS-2B Cells to Nontoxic and Toxic Chromium: Protein Indicators of Cytotoxicity Conversion. TOXICOLOGY LETTERS. Elsevier Science Ltd, New York, NY, 264:59-70, (2016).
This research grew out of our previous ACE task 192 research to address mixture toxicity characterization using an integrated proteomics approach. One of the objectives was to demonstrate that proteomic methods and technology platforms could be used to identify biochemical and toxicity pathways specific to individual metals and mixtures. This manuscript describes biochemical and toxicity pathways specific to cytotoxicity of chromium (Cr (VI)).
Hexavalent chromium (Cr (VI)) is an environmental human carcinogen which primarily targets lungs. Among a variety of toxic mechanisms, disruption of biological pathways via translational and post-translational modifications represents a key mechanism through which Cr (VI) induces cytotoxicity and carcinogenesis. To identify those disruptions which are altered in response to cytotoxic Cr (VI) exposures, we measured and compared cytotoxicity and changes in expression and phosphorylation status of 15 critical biochemical pathway regulators in human BEAS-2B cells exposed for 48 h to a non-toxic concentration (0.3 µM) and a toxic concentration of (1.8 μM) Cr (VI) by ELISA techniques. In addition, 43 functional proteins which may be altered in response to pathway signaling changes were identified using two dimensional electrophoresis (2-DE) and mass spectrometry. The proteins and fold changes observed in cells exposed to the non-toxic dose of Cr (VI) (0.3μM) were not necessarily the same as those found in the toxic one (1.8 μM). A subset of signaling proteins that were correlated with the cytotoxic responses of human BEAS-2B cells to Cr (VI) treatments include regulators of glycolysis (GSK3β and P70S6K), a signaling protein associated with oxidative stress and inflammation responses (JNK), a metal responsive transcription factor (MTF-1), and polyubiquitin C (UBC), a source of ubiquitin for signaling targeted protein degradation. In addition, key alterations in biochemical pathways differentiating between cytotoxic and non-cytotoxic exposures to Cr (VI) were identified, including glycolysis and gluconeogenesis, protein degradation, inflammation, and response to oxidative stress.