Although arsenic is acknowledged to be highly carcinogenic to human skin, its action at the cellular and molecular level is not well understood. It is thought that arsenite-induced cell proliferation is one of the central events involved in its carcinogenic activity. Our preliminary data have revealed that treatment of cells with arsenite results in the activation of phosphatidylinositol 3-kinase (PI-3K) and downstream kinases, protein kinase B (Akt) and p70 S6 kinase (p70S6k), as well as an increase in cyclin D1 induction, cell proliferation and transformation in human keratinocytes. Considering the essential role of PI-3K and its downstream kinases in cyclin D1 induction, cell proliferation and transformation, the main hypothesis of this proposal is that PI-3K and its downstream signaling pathways play a pivotal role in arsenite-induced cyclin D1 expression, cell proliferation and transformation in human keratinocytes. The long-term goal is to elucidate the molecular mechanisms by which arsenite causes human skin cancer development. The overall aim of this proposal is to test the effect of arsenite on the PI-3K signal transduction pathway and its role in the regulation of cyclin D1 expression, cell proliferation and transformation in human keratinocytes. Especially, we will investigate this issue in accordance with the following testable hypotheses and specific aims (SA): SA 1: To test the hypothesis that PI-3K is required for the activation of Akt and p70S6k in arsenite-treated human keratinocytes. SA 2: To investigate whether PI- 3K/Akt/p70 s6k pathway plays a role in arsenite-induced cyclin D1 expression and cell proliferation in human keratinocytes. SA 3: To test the hypothesis that PI-3K/Akt/p70S6k pathway plays a role in arsenite-induced cell transformation in human keratinocytes. SA 4: To test the hypothesis that AP-1 and/or NFkappaB are downstream transcription factor(s) in human keratinocytes response to arsenite treatment. SA 5: To test the hypothesis that activation of AP-1 and/or NFkappaB is required for induction of cyclin D1 expression, cell proliferation and cell transformation by arsenite in HaCat cells. The significance of the research proposed in this application is that the results derived from the proposed studies will greatly facilitate the understanding of the molecular mechanism of cancer development caused by arsenite in human skin. A better understanding of signal transduction pathways leading to the induction of cyclin D1 expression, cell proliferation and transformation, will provide valuable information needed for designing more effective agents for the prevention and therapy of cancers caused by arsenite. Such agents could interfere with signaling pathways leading to cyclin D1 induction, cell proliferation and cell transformation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094964-02
Application #
6879709
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Yang, Shen K
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$277,160
Indirect Cost
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Zhang, Dongyun; Li, Jingxia; Costa, Max et al. (2010) JNK1 mediates degradation HIF-1alpha by a VHL-independent mechanism that involves the chaperones Hsp90/Hsp70. Cancer Res 70:813-23
Luo, Wenjing; Li, Jingxia; Zhang, Dongyun et al. (2010) Bid mediates anti-apoptotic COX-2 induction through the IKKbeta/NFkappaB pathway due to 5-MCDE exposure. Curr Cancer Drug Targets 10:96-106
Song, Lun; Dong, Wen; Gao, Ming et al. (2010) A novel role of IKKalpha in the mediation of UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression. Biochim Biophys Acta 1803:323-32
Ding, Jin; Ning, Beifang; Huang, Yi et al. (2009) PI3K/Akt/JNK/c-Jun signaling pathway is a mediator for arsenite-induced cyclin D1 expression and cell growth in human bronchial epithelial cells. Curr Cancer Drug Targets 9:500-9
Yu, Yonghui; Wan, Yu; Huang, Chuanshu (2009) The biological functions of NF-kappaB1 (p50) and its potential as an anti-cancer target. Curr Cancer Drug Targets 9:566-71
Ouyang, Weiming; Zhang, Dongyun; Li, Jingxia et al. (2009) Soluble and insoluble nickel compounds exert a differential inhibitory effect on cell growth through IKKalpha-dependent cyclin D1 down-regulation. J Cell Physiol 218:205-14
Zhang, Dongyun; Li, Jingxia; Gao, Jimin et al. (2009) c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells. Toxicol Appl Pharmacol 235:18-24
Yang, Z; Song, L; Huang, C (2009) Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 9:915-30
Song, Lun; Li, Jingxia; Hu, Meiru et al. (2008) Both IKKalpha and IKKbeta are implicated in the arsenite-induced AP-1 transactivation correlating with cell apoptosis through NF-kappaB activity-independent manner. Exp Cell Res 314:2187-98
Luo, Wenjing; Liu, Jinyi; Li, Jingxia et al. (2008) Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway. J Biol Chem 283:8624-33

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