This is a competitive renewal application to investigate the molecular mechanisms of the chemopreventive effect of cancer by tea polyphenols. During the previous funding period, we investigated the effect of tea polyphenols on various protein kinases and AP-1 and NF-kappaB signal transduction pathways in cell culture and genetically-modified mouse models. We found that tea polyphenols (-)-epigallocatechin 3-gallate (EGCG) and theaflavins inhibited tumor promoter-induced or oncogene-induced protein kinases and multiple signal transduction pathways. The dose range of these tea polyphenols that effectively inhibited these signals is similar to that which can inhibit cell transformation and skin carcinogenesis. In this renewal proposal, we hypothesize that Pin-1 acts as a central hub in mediating the anticancer effects of tea polyphenols on multiple signal transduction pathways. This hypothesis is based on our other published data and our preliminary data showing that (a) Pin-1 is critical for neoplastic cell transformation and tumorigenesis;(b) EGCG can bind with Pin-1;(c) EGCG and other tea polyphenols inhibit multiple signal transduction pathways AP-1, NF-kappaB, and NFAT;(d) Pin-1 is one of the core proteins that can regulate all of these distinct signaling pathways. To test this hypothesis, we will use state-of-the-art technologies such as X-ray crystallography, protein chemistry, molecular biology, cell culture and knockout mouse models with the following Specific Aims:
Specific Aim 1. To study the role of Pin-1 in the inhibitory activity of EGCG on cell transformation in vitro.
Specific Aim 2. To study the interactions of EGCG and other tea polyphenols with Pin-1.
Specific Aim 3. To study the role of Pin-1 as a molecular target for the anti-tumor effect of EGCG in vivo in a tumor xenograft model. We have established experimental conditions through preliminary investigations and expect that the proposed molecular mechanism studies will lead to development of better chemopreventive agents and facilitate the design of more effective chemoprevention trials.

Public Health Relevance

Many studies have shown the anti-cancer effect of drinking green and black tea in both laboratory studies and human population studies. However, the mechanisms of the anti-cancer effect of tea are not clear. This study is to identify the molecular mechanisms/targets associated with the anti-cancer effects exhibited by tea. Such knowledge will help to develop better cancer preventing agens and design more effective cancer prevention trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Kopelovich, Levy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Organized Research Units
United States
Zip Code
Sheng, Yuqiao; Liu, Kangdong; Wu, Qiong et al. (2016) PPMP, a novel tubulin-depolymerizing agent against esophageal cancer in patient-derived tumor xenografts. Oncotarget 7:30977-89
Li, Yan; Dong, Zigang (2016) Effect of Clustering Algorithm on Establishing Markov State Model for Molecular Dynamics Simulations. J Chem Inf Model 56:1205-15
Kim, Dong Joon; Roh, Eunmiri; Lee, Mee-Hyun et al. (2016) Herbacetin Is a Novel Allosteric Inhibitor of Ornithine Decarboxylase with Antitumor Activity. Cancer Res 76:1146-1157
Peng, C; Zeng, W; Su, J et al. (2016) Cyclin-dependent kinase 2 (CDK2) is a key mediator for EGF-induced cell transformation mediated through the ELK4/c-Fos signaling pathway. Oncogene 35:1170-9
Kim, Jong-Eun; Kim, Jae Hwan; Lee, Younghyun et al. (2016) Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase. Oncotarget 7:14616-27
Bode, Ann M; Dong, Zigang; Wang, Hongyang (2016) Cancer prevention and control: alarming challenges in China. Natl Sci Rev 3:117-127
Lim, Do Young; Shin, Seung Ho; Lee, Mee-Hyun et al. (2016) A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer. Oncotarget 7:35001-14
Kim, J-E; Roh, E; Lee, M H et al. (2016) Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis. Oncogene 35:4091-101
Zhang, C; Liu, K; Yao, K et al. (2015) HOI-02 induces apoptosis and G2-M arrest in esophageal cancer mediated by ROS. Cell Death Dis 6:e1912
Liu, Kangdong; Park, Chanmi; Chen, Hanyong et al. (2015) Eupafolin suppresses prostate cancer by targeting phosphatidylinositol 3-kinase-mediated Akt signaling. Mol Carcinog 54:751-60

Showing the most recent 10 out of 106 publications