 |
|
Jill C. Pelling, PhD
Professor of Pathology
Associate Director for Translational Research
Robert H. Lurie Comprehensive Cancer Center
Molecular mechanisms of chemoprevention; signal transduction pathways in UV response; role of hypoxia in carcinogenesis
Curricula:
Cancer Biology
Pharmacology and Toxicology
E-mail: j-pelling@northwestern.edu |
A major focus of investigation in my laboratory is the area of chemoprevention of cancer. In recent years there has been a great deal of scientific interest in identifying the dietary factors which may prove useful in preventing cancer in various organ sites. We are presently working with a plant flavonoid called Apigenin, which is present in leafy vegetables and fruits, and has been shown to inhibit UV- and chemically-induced mouse skin tumorigenesis. Studies in our laboratory have demonstrated that Apigenin has multiple modes of action in cells, including the ability to induce G1 and G2/M cell cycle arrest, to induce apoptosis, to inhibit various signaling pathways important in tumor growth including cyclooxygenase and Akt, and to inhibit the expression of hypoxia inducing factor (HIF1-alpha). These studies are relevant to several areas of biomedical research, including cancer biology, angiogenesis, cell signaling and development of novel chemopreventive agents against cancer.
The focus of our work is in three areas:
Inhibition of UVB-induced COX-2 expression by apigenin: Cyclooxygenase-2 (COX-2) is overexpressed in many different types of cancer, and thus represents a critical target for therapy and prevention. We have demonstrated that Apigenin is a potent inhibitor of UV-induced COX-2 expression in keratinocytes, at both the transcriptional and post-transcriptional level. We are currently investigating the trans-acting factors that bind to the 3’untranslated region (UTR) of COX-2 mRNA, thereby affecting message stability and modulating translational efficiency.
Signal transduction response of keratinocytes to UV-B irradiation: The UV response of cells includes activation of a number of signaling pathways, including activation of the stress-activation protein kinases (SAPK/JNK) as well as induction of p53 protein levels and transcriptional activation of its downstream targets such as p21WAF cyclin inhibitor and MDM2. Our laboratory is currently studying ways in which cell cycle regulatory proteins interact with and are modulated by the Akt pathway.
Hypoxia inducing factor (HIF1-alpha) expression is inhibited by Apigenin: A new project in our laboratory focuses on the mechanisms by which Apigenin inhibits HIF1-alpha expression in prostate cancer cells throught an Akt-mediated pathway.
Publications:
McVean, M., Xiao, H., Isobe, K., and Pelling, J.C. Increase in wildtype p53 stability and transactivational activity by the chemopreventive agent apigenin in keratinocytes. Carcinogenesis 21:633-639, 2000.
Persons, D.L., Yazlovitskaya, E.M. and Pelling, J.C. Extracellar signal-regulated kinase (ERK) activity and regulation of p53 protein accumulation during exposure to cisplatin. J. Biol. Chem. 275:35778-35785, 2000.
Xue, Yue, Hong, X., and Pelling, J.C. JNK associates with p21waf1 and p53: Modulation of JNK activity. Molecular Carcinogenesis 36:38-44, 2002
Van Dross, R., Xue, Y., Knudson, A., and Pelling, J.C. Modulation of MAPK signal transduction pathways by the bioflavonoid apigenin. J. Nutrition 133:3800-3804, 2003.
Van Dross, R., Hong, X., and Pelling, J.C. Inhibition of TPA-induced cyclooxygenase-2 (COX-2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes. Molecular Carcinogenesis 44:83-91, 2005.
