Reactive oxygen species regulate properties of transformation in UROtsa cells exposed to monomethylarsonous acid by modulating MAPK signaling |
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| Authors: | K.E. Eblin T.J. Jensen S.M. Wnek S.E. Buffington B.W. Futscher A.J. Gandolfi |
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| Affiliation: | 1. Department of Pharmacology and Toxicology, University of Arizona, United States;2. Arizona Cancer Center, University of Arizona, United States;1. Department of Pathology and Microbiology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, NE 68198-3135, USA;2. Compound Safety Prediction, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA;3. Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE 68198-4375, USA;4. Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198-5125, USA;1. The Key Laboratory of Gene Engineering of Education Ministry, Sun Yat-sen University, Guangzhou 510275, PR China;2. Department of Social and Preventive Medicine, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA;3. Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Prevention and Treatment Center for Occupational Diseases, Guangzhou 510300, PR China;4. Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214, USA;5. Department of Biochemistry and Center of Excellence in Bioinformatics and Life Sciences, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214, USA;1. The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, Albuquerque, NM 87131, United States;2. Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, United States;1. Laboratory of Environmental Toxicology and Carcinogenesis, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan;2. Research Center for Occupational Poisoning, Kansai Rosai Hospital, Hyogo 660-8511, Japan;3. Department of Preventive Medicine and Environmental Health, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan;1. Centre for Biomolecular Interactions Bremen, University of Bremen, P.O. Box 330440, D-28334 Bremen, Germany;2. Centre for Environmental Research and Sustainable Technology, Leobener Strasse, D-28359 Bremen, Germany;1. Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany;2. Institute of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131 Mainz, Germany |
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| Abstract: | ![]()
UROtsa cells exposed to 50 nM monomethylarsonous acid [MMA(III)] for 52 wk (MSC52) achieved hyperproliferation, anchorage independent growth, and enhanced tumorgenicity. MMA(III) has been shown to induce reactive oxygen species (ROS), which can lead to activation of signaling cascades causing stress-related proliferation of cells and even cellular transformation. Previous research established the acute activation of MAPK signaling cascade by ROS produced by MMA(III) as well as chronic up regulation of COX-2 and EGFR in MSC52 cells. To determine if ROS played a role in the chronic pathway perturbations by acting as secondary messengers, activation of Ras was determined in UROtsa cells [exposed to MMA(III) for 0–52 wk] and found to be increased through 52 wk most dramatically after 20 wk of exposure. Ras has been shown to cause an increase in O2? and be activated by increases in O2?, making ROS important to study in the transformation process. COX-2 upregulation in MSC52 cells was confirmed by real time RT-PCR. By utilizing both antioxidants or specific COX inhibitors, it was shown that COX-2 upregulation was dependent on ROS, specifically, O2?. In addition, because previous research established the importance of MAPK activation in phenotypic changes associated with transformation in MSC52 cells, it was hypothesized that ROS play a role in maintaining phenotypic characteristics of the malignant transformation of MSC52 cells. Several studies have demonstrated that cancer cells have lowered superoxide dismutase (MnSOD) activity and protein levels. Increasing levels of MnSOD have been shown to suppress the malignant phenotype of cells. SOD was added to MSC52 cells resulting in slower proliferation rates (doubling time = 42 h vs. 31 h). ROS scavengers of  OH also slowed proliferation rates of MSC52 cells. To further substantiate the importance of ROS in these properties of transformation in MSC52 cells, anchorage independent growth was assessed after the addition of antioxidants, both enzymatic and non-enzymatic. Scavengers of OH, and O2? blocked the colony formation of MSC52 cells. These data support the role for the involvement of ROS in properties of transformation of UROtsa cells exposed to MMA(III). |
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