Apigenin is a nonmutagenic bioflavonoid that inhibits UV-induced skin cancer when topically applied to mouse skin and we are currently investigating its molecular mechanism(s) of action. Recent results from our laboratory indicate that inhibition of the cyclooxygenase-2 (COX-2) pathway is one of the ways that apigenin exerts its chemopreventive effect. We have demonstrated that apigenin is a specific inhibitor of UV-induced cyclooxygenase-2 (COX-2) transcription in UV-induced keratinocytes. We have also obtained new evidence since the previous submission that UV-induction of COX-2 expression in keratinocytes requires the E-box and ATF/CRE transcription factor binding sites in the first 200 bases of the COX-2 promoter region, as well as demonstrating a role for the NF-IL6 site. These results suggest that one mechanism by which apigenin inhibits UV-induced skin carcinogenesis is by modulating the function of DNA binding proteins specific for these sites. Recent reports from other laboratories including our collaborator Dr. Aubrey Morrison indicate that COX-2 expression is regulated post-transcriptionally as well, by trans-acting factors which affect COX-2 mRNA stability and modulate translational efficiency. Therefore the hypothesis to be tested in this revised application is that one of the mechanisms by which the bioflavonoid apigenin inhibits UV-induced skin carcinogenesis is through modulation of transcriptional and post-transcriptional control of COX-2 expression. The following aims will test this hypothesis:
In Aim #1 we will continue our efforts to identify the DNA binding proteins in the COX-2 promoter required for UVB-induced COX-2 transcription and for inhibition by apigenin in keratinocytes and mouse epidermis in vivo.
In Aim #2 we will investigate the mechanism by which apigenin treatment of keratinocytes modulates the function of the DNA binding proteins identified in Aim #1.
In Aim #3 we will characterize the post-transcriptional control mechanisms which affect UVB-induced COX-2 expression in keratinocytes treated with apigenin, using regions of the COX-2 3'-UTR to investigate apigenin's ability to interfere with UV-induced mRNA stabilization and/or translational efficiency.
In Aim #4 we will use SKH-1 mice and SKH-1 COX-2 null mice to confirm the ability of apigenin to block UVB-induced COX-2 expression and tumorigenesis in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA104768-01A1
Application #
6831577
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$300,642
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tong, Xin; Pelling, Jill C (2013) Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention. Anticancer Agents Med Chem 13:971-8
Tong, Xin; Smith, Kimberly A; Pelling, Jill C (2012) Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes. Mol Carcinog 51:268-79
Smith, Kimberly A; Tong, Xin; Abu-Yousif, Adnan O et al. (2012) UVB radiation-induced ?-catenin signaling is enhanced by COX-2 expression in keratinocytes. Mol Carcinog 51:734-45
Tong, Xin; Pelling, Jill C (2009) Enhancement of p53 expression in keratinocytes by the bioflavonoid apigenin is associated with RNA-binding protein HuR. Mol Carcinog 48:118-29
Abu-Yousif, Adnan O; Smith, Kimberly A; Getsios, Spiro et al. (2008) Enhancement of UVB-induced apoptosis by apigenin in human keratinocytes and organotypic keratinocyte cultures. Cancer Res 68:3057-65
Van Dross, Rukiyah T; Hong, Xiaoman; Essengue, Suzanne et al. (2007) Modulation of UVB-induced and basal cyclooxygenase-2 (COX-2) expression by apigenin in mouse keratinocytes: role of USF transcription factors. Mol Carcinog 46:303-14
Tong, Xin; Van Dross, Rukiyah T; Abu-Yousif, Adnan et al. (2007) Apigenin prevents UVB-induced cyclooxygenase 2 expression: coupled mRNA stabilization and translational inhibition. Mol Cell Biol 27:283-96