Aspirin is one of the most promising agents for the chemoprevention of human cancer. The clinical usefulness of aspirin is partially limited by its side effects. The overall aim of this research proposal is to test the hypothesis that transcription factor AP-1 is the molecular target for the anti-tumor promotion effect of aspirin in JB6 cells and an AP-1- luciferase transgenic mouse model. This mechanism may also be applicable to other systems, in addition to or instead of the """"""""prostaglandin H synthase inhibition"""""""" mechanism, for the anti-tumor promotion activity of aspirin. Such knowledge will help to develop better agents with fewer side effects for effective chemoprevention of human cancer.
The specific aims are:
Aim 1 - To determine whether inhibition of tumor promoter-induced cell transformation by aspirin is dependent on the inhibition of AP-1 activity;
Aim 2 - To determine whether prostaglandin H synthase is involved in the inhibiition of tumor promoter-induced AP-1 activity and cell transformation by aspirin or salicylic acid;
Aim 3 - To determine whether inhibition of AP-1 acitivity and transformation of aspirin is through a mitogen- activated protein kinase (MAP kinase) pathway or through the elevation of intracellular H plus concentration;
Aim 4 - To determine whether aspirin inhibits AP-1 activity and tumor promotion in vivo under the two-stage carcinogenesis conditions in an AP-1 luciferase transgenic mouse model. The strategy for Specific Aim 1 is to establish a cell culture model for studying anti-tumor promotion activity of aspirin by using the JB6 cell system. We will then test whether AP-1 activity is inhibited in the same anti-tmor promotion conditions. We will also test the activity of anti-tumor promotion and inhibition of AP-1 by other nonsteroidal anti-inflammatory drugs (NSAIDs). For Specific Air 2, we will use indomethacin and other NSAIDs, which do not inhibit AP-1 activity and are potent prostaglandin H synthase inhibitors to test whether they inhibit or promote JB6 cell transformation. We will alos test the direct effect of prostaglandins on AP-1 activity and cell transformation.
For Specific Aim 3, we will use antibodies specific for the phosphorylated tyrosine 204 of Erk1 or Erk2, and Ser63 or Ser73 of c-Jun to study the phosphorylated Erk1 or Erk2, c-Jun (Ser63/Ser73) and JNK activity. We will measure the effect of aspirin on intracellular pH by a pH dependent fluorescence dye and study the role of intrascellular pH on AP-1 activity and cell transformation by using a H plus pump inhibitor, diethylstilbestrol and overexpression of ATPase PMA gene and its mutants in JB6 cells.
For Specific Aim 4, we will use an AP-1 luciferase transgenic mouse model to investigate whether aspirin inhibits AP-1 activity in vivo under the two-stage carcinogenesis conditions. Furthermore, we will test whether the same dosage of aspirin that inhibits tumor promoter-induced AP-1 activity also inhibits tumor promotion in the transgenic mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA074916-01
Application #
2372133
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1997-07-11
Project End
2002-06-30
Budget Start
1997-07-11
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cho, Yong-Yeon; Tang, Faqing; Yao, Ke et al. (2009) Cyclin-dependent kinase-3-mediated c-Jun phosphorylation at Ser63 and Ser73 enhances cell transformation. Cancer Res 69:272-81
Tang, Faqing; Liu, Guangming; He, Zhiwei et al. (2006) Arsenite inhibits p53 phosphorylation, DNA binding activity, and p53 target gene p21 expression in mouse epidermal JB6 cells. Mol Carcinog 45:861-70
Bode, Ann M; Dong, Zigang (2006) Molecular and cellular targets. Mol Carcinog 45:422-30
Bode, Ann M; Dong, Zigang (2005) Signal transduction pathways in cancer development and as targets for cancer prevention. Prog Nucleic Acid Res Mol Biol 79:237-97
Liu, Guangming; Ma, Wei-Ya; Bode, Ann M et al. (2003) NS-398 and piroxicam suppress UVB-induced activator protein 1 activity by mechanisms independent of cyclooxygenase-2. J Biol Chem 278:2124-30
Park, Ann M; Dong, Zigang (2003) Signal transduction pathways: targets for green and black tea polyphenols. J Biochem Mol Biol 36:66-77
Bode, Ann M; Dong, Zigang (2003) Mitogen-activated protein kinase activation in UV-induced signal transduction. Sci STKE 2003:RE2
Dong, Zigang; Bode, Ann M (2003) Dialogue between ERKs and JNKs: friendly or antagonistic? Mol Interv 3:306-8
She, Qing-Bai; Chen, Nanyue; Bode, Ann M et al. (2002) Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 62:1343-8
Liu, Guangming; Zhang, Yiguo; Bode, Ann M et al. (2002) Phosphorylation of 4E-BP1 is mediated by the p38/MSK1 pathway in response to UVB irradiation. J Biol Chem 277:8810-6

Showing the most recent 10 out of 50 publications