Arsenic (As) is a well-documented human carcinogen. Environmental and occupational exposures to As-containing compounds are major public health issues. Understanding the mechanism of As-induced carcinogenesis is very important for early detection, for risk assessment, for establishment of an exposure standard, and for development of intervention and prevention strategies. While increasing evidence has linked arsenic exposure and generation of reactive oxygen species (ROS), we do not clearly understand the exact nature of the specific reactive species, the source and mechanism of ROS generation, the sequence of formation of different reactive species, and the specific species that are responsible for the arsenic-induced carcinogenesis. The goal of this proposal is to test the hypothesis that As-induced carcinogenesis is mediated by oxidative stress. To test this hypothesis, we will: (a) identify the molecular mechanism of As-induced ROS generation in cells with emphasis on 02.- radical generation since this radical is a precursor of other reactive oxygen species;(b) develop and apply an in vivo electron spin resonance (ESR) method for detection and identification of As-induced free radical generation in living animals;(c) determine oxidative stress, lipid peroxidation, protein oxidation, and oxidative DNA damage following As exposure in vivo;and (d) elucidate the role of oxidative stress in Cr(VI)-induced cell transformation and tumorigenesis. We will use As-treated HaCat cells to examine As-induced tumorigenesis in athymic nude mice and investigate the involvement of specific ROS species. We anticipate that As generates ROS, which cause activation of NF-KB and activator protein (AP-1) leading to tumorigenesis in nude mice. The methods used in the proposal are multi-disciplinary representing a combination of physical, chemical, and molecular approaches. The results obtained from this proposal will provide a fundamental understanding concerning the role of ROS in As-induced carcinogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-E (02))
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Blair, Donald G
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University of Kentucky
Schools of Medicine
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Son, Young-Ok; Pratheeshkumar, Poyil; Divya, Sasidharan Padmaja et al. (2017) Nuclear factor erythroid 2-related factor 2 enhances carcinogenesis by suppressing apoptosis and promoting autophagy in nickel-transformed cells. J Biol Chem 292:8315-8330
Wang, Lei; Hitron, John Andrew; Wise, James T F et al. (2015) Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-?B signalings in colorectal cancer cells. Toxicol Appl Pharmacol 288:232-9
Son, Young-Ok; Pratheeshkumar, Poyil; Roy, Ram Vinod et al. (2014) Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis. J Biol Chem 289:28660-75
Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja et al. (2014) Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways. Toxicol Appl Pharmacol 281:230-41
Ding, Song-Ze; Yang, Yu-Xiu; Li, Xiu-Ling et al. (2013) Epithelial-mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells. Toxicol Appl Pharmacol 269:61-71
Yang, Yu-Xiu; Li, Xiu-Ling; Wang, Lei et al. (2013) Anti-apoptotic proteins and catalase-dependent apoptosis resistance in nickel chloride-transformed human lung epithelial cells. Int J Oncol 43:936-46
Wang, Xin; Mandal, Ardhendu K; Saito, Hiroshi et al. (2012) Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/?-catenin signaling pathway. Toxicol Appl Pharmacol 262:11-21
Liu, Jinyi; Zhang, Dongyun; Luo, Wenjing et al. (2012) E3 ligase activity of XIAP RING domain is required for XIAP-mediated cancer cell migration, but not for its RhoGDI binding activity. PLoS One 7:e35682
Nguyen Ngoc, Tam Dan; Son, Young-Ok; Lim, Shin-Saeng et al. (2012) Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways. Toxicol Appl Pharmacol 259:329-37
Son, Young-Ok; Wang, Lei; Poyil, Pratheeshkumar et al. (2012) Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3?/?-catenin signaling. Toxicol Appl Pharmacol 264:153-60

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