Nickel-containing compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. Recent studies have indicated that reactive oxygen species (ROS) may play an important role. We hypothesize that nickel induces generation of ROS, which activate nuclear transcription factors, leading to cell transformation and tumorigenesis.
Specific Aim 1 will detect and identify ROS generated in human bronchial epithelial cells (BEAS-2B) and mouse embryo fibroblast cells exposed to nickel compounds and investigate the mechanism involved. We hypothesize that nickel (Ni3S2 and NiCl2) can stimulate the cells to activate NADPH oxidase via cdc42 and p47phox to produce superoxide radical, which is then converted to hydrogen peroxide and hydroxyl radical.
Specific Aim 2 will test the hypothesis that ROS are required for activation of NFAT and NFkappaB in cells and in vivo in response to nickel compounds. The role of ROS in nickel-induced activation of NFAT and NFkappaB in cells will be evaluated by co-transfection of NFkappaB-luciferase or NFAT-luciferase reporter plasmids and specific ROS scavenger enzymes. For in vivo study, BALB/c transgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROS generating enzyme) will be employed.
Specific Aim 3 will Investigate the role of ROS, NFAT and NFkappaB in nickel-induced cell transformation and tumorigenesis. We hypothesize that ROS activate transcription factors and cause cell transformation and tumorigenesis. We will use overexpression of DN-NFAT, DN-IkappaBalpha and DN- IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-cell transformation and induced tumorigenesis. The role of ROS will be investigated using specific antioxidant enzyme expressions and NADPH oxidase alternation. We anticipate that nickel causes activation of NFAT and NFkappaB through ROS reactions, leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species. The results obtained from this proposal will elucidate the role of ROS and NFAT/NFkappaB signaling in Ni compounds-induced carcinogenesis. The long term goals are to provide a fundamental understanding concerning the mechanism of carcinogenic actions of Ni;to fill a need for the mechanistic information of cancer risk assessment for exposure;to propose methods for early detection;and to develop intervention and prevention strategies. Nickel-containing compounds are human carcinogens. This project will investigate the mechanism of Ni-induced carcinogenesis by testing the hypothesis that nickel induces generation of ROS, which activate nuclear transcription factors, leading to cell transformation and tumorigenesis. The long term goals are to understand the mechanism of Ni-carcinogenesis;to propose methods for early detection;and to develop intervention and prevention strategies.
|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|
|Roy, Ram Vinod; Pratheeshkumar, Poyil; Son, Yong-Ok et al. (2016) Different roles of ROS and Nrf2 in Cr(VI)-induced inflammatory responses in normal and Cr(VI)-transformed cells. Toxicol Appl Pharmacol 307:81-90|
|Roy, Ram Vinod; Son, Young-Ok; Pratheeshkumar, Poyil et al. (2015) Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis. J Environ Pathol Toxicol Oncol 34:63-84|
|Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin et al. (2014) Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-?B signaling pathways in SKH-1 hairless mice skin. Toxicol Appl Pharmacol 280:127-37|
|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|
|Wang, Lei; Kuang, Lisha; Hitron, John Andrew et al. (2013) Apigenin suppresses migration and invasion of transformed cells through down-regulation of C-X-C chemokine receptor 4 expression. Toxicol Appl Pharmacol 272:108-16|
|Son, Young-Ok; Pratheeshkumar, Poyil; Wang, Lei et al. (2013) Reactive oxygen species mediate Cr(VI)-induced carcinogenesis through PI3K/AKT-dependent activation of GSK-3?/?-catenin signaling. Toxicol Appl Pharmacol 271:239-48|
|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|
|Wang, Lei; Son, Young-Ok; Ding, Songze et al. (2012) Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway. Toxicol Sci 130:269-80|
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