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¹ Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, State University of New Jersey, Piscataway, New Jersey and ² Department of Pediatrics and ³ Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey

Requests for reprints: Khew-Voon Chin, Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 253; Fax: 732-445-0687. E-mail: chinkv{at}rci.rutgers.edu

Many studies suggest green tea is a cancer chemopreventive agent. This effect has been attributed to its major constituent (–)-epigallocatechin-3-gallate (EGCG). EGCG is also observed to have cytotoxic anticancer effects, especially when used in combination with certain chemotherapeutic agents. The biochemical actions of EGCG in chemoprevention and anticancer effects have been studied; however, the mechanisms of action are not clearly understood. We show here by expression genomics the effects of EGCG (25 µmol/L) in the Ha-ras gene transformed human bronchial epithelial 21BES cells. We found induction of temporal changes in gene expression and the coalescence of specific genetic pathways by EGCG. In this experimental system, hydrogen peroxide (H₂O₂) was produced. By treating cells with EGCG in the presence or absence of catalase, we further distinguished gene expression changes that are mediated by H₂O₂ from those that are H₂O₂ independent. Many genes and cellular pathways, including genes of the transforming growth factor-ß signaling pathway, were H₂O₂ dependent because the effects were abolished by catalase. Gene expression changes that were not affected by catalase included those of the bone morphogenetic protein signaling pathway, peptidylprolyl isomerase (cyclophilin)–like 2, alkylated DNA repair enzyme alkB, polyhomeotic-like 2, and homeobox D1. We show further that EGCG and H₂O₂ differentially transactivated the bone morphogenetic protein and the transforming growth factor-ß response element promoter reporters, respectively, thus confirming results from DNA microarray analysis. The elucidation of gene expression changes between H₂O₂-dependent and H₂O₂-independent responses helps us better understand the cancer chemopreventive and anticancer actions of EGCG.

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Received 3/15/04; revised 5/25/04; accepted 6/30/04.