title: EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells.
abstract: Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
authors.affiliation: Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Atsuko
authors.initials: A
authors.lastname: Deguchi
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Joe
authors.forename: Judith F
authors.initials: JF
authors.lastname: Mckoy
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: I Bernard
authors.initials: IB
authors.lastname: Weinstein
mesh_terms: D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D016328:NF-kappa B / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016328:NF-kappa B; D012334:RNA, Neoplasm; D018808:Transcription Factor AP-1; D051020:bcl-X Protein; D002392:Catechin; C045651:epigallocatechin gallate; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D015232:Dinoprostone