Hexavalent chromium [Cr(VI)] is a known environmental carcinogen. Environmental exposure to Cr(VI)-containing compounds causes cancers of various organs. Its mechanism of carcinogenic actions remains to be investigated. Recent studies have demonstrated that reduction of Cr(VI) to its lower oxidation states is important for Cr(VI)-induced carcinogenesis. It has been shown that cellular reduction of Cr(VI) generates reactive oxygen species (ROS) which cause various cellular injuries. We hypothesize that Cr(VI) induces generation of ROS, which activate nuclear transcription factors, leading to cell transformation and tumorigenesis.
In Specific Aim 1, we will identify ROS generated in Cr(VI) treated human lung bronchial epithelial (BEAS-2B) cells and the mechanism involved. We will emphysize the role of CDC42 signaling and the involvement of p47phox and NADPH oxidases in the molecular mechanism of Cr(VI)-induced ROS production.
In Specific Aim 2, we will detect reactive Cr(V) intermediates produced in Cr(VI) reduction by living animals and identify the chemical structures of these intermediates. We will also detect and identify superoxide (O2'-) and hydroxyl ('OH) radicals produced by intact animals exposed to Cr(VI). Major methods to be used in this aim are low frequency electron spin resonance (ESR) spectroscopy and ESR spin trapping.
In Specific Aim 3, we will investigate Cr(VI)-induced activation of NF-kappaB and AP-1 in BEAS-2B cells and in transgenic mice. We will use a dominant negative mutant MEK1/2, a dominant negative mutant ERK2, or a dominant negative mutant c-jun (TAM67), respectively, to investigate the role of the MEK1/2-ERKs-AP-1 pathway in Cr(VI)-induced cell transformation. We will also use a dominant negative mutant IkappaBa or a dominant negative mutant IKK?, respectively, to determine the role of the IKK?-lkappaBa-NF-kappaB pathway in Cr(VI)-induced cell transformation. The involvement of ROS in these pathways will be investigated using expressions of specific antioxidant enzymes. Tumorigenesis will be investigated by injecting the transformed cells into athymic nude mice. We anticipate that Cr(VI) causes activation of transcription factors 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-T (04))
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Blair, Donald G
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University of Kentucky
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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
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
Choe, Youngji; Yu, Ji-Yeon; Son, Young-Ok et al. (2012) Continuously generated H2O2 stimulates the proliferation and osteoblastic differentiation of human periodontal ligament fibroblasts. J Cell Biochem 113:1426-36
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
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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