title: The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model.
abstract: (-)-Epigallocatechin gallate (EGCG), a major tea polyphenol, elicits anticancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We used nontumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer progression model to test the hypotheses that certain stages are more or less sensitive to EGCG and that sensitivity is related to HSP90 inhibition. Treatment of cells with EGCG, novobiocin, or 17-AAG resulted in more potent cytotoxic effects on tumorigenic and metastatic cells than NT cells. When tumorigenic or metastatic cells were grown in vivo, mice supplemented with 0.06% EGCG in drinking water developed significantly smaller tumors than untreated mice. Furthermore, EGCG prevented malignant transformation in vivo using the full prostate cancer model. To elucidate the mechanism of EGCG action, we performed binding assays with EGCG-Sepharose, a C-terminal HSP90 antibody, and HSP90 mutants. These experiments revealed that EGCG-Sepharose bound more HSP90 from metastatic cells compared with NT cells and binding occurred through the HSP90 C-terminus. In addition, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, novobiocin, and 17-AAG induced changes in HSP90-client proteins in NT cells and larger differences in metastatic cells. These data suggest that EGCG may be efficacious for the treatment of prostate cancer because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moses
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Henry
authors.affiliation: Department of Urology, Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Madison, Wisconsin.
authors.forename: William A
authors.initials: WA
authors.lastname: Ricke
authors.affiliation: Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York. tom_gasiewicz@urmc.rochester.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gasiewicz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D002392:Catechin; C045651:epigallocatechin gallate