The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model
| Autor: | William A. Ricke, Ellen C. Henry, Thomas A. Gasiewicz, Michael A. Moses |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Cancer Research Blotting Western Prostatic Hyperplasia Antineoplastic Agents Apoptosis Biology Epigallocatechin gallate Real-Time Polymerase Chain Reaction complex mixtures Catechin Article Malignant transformation Metastasis Mice chemistry.chemical_compound Cell Movement Heat shock protein Tumor Cells Cultured polycyclic compounds medicine Animals Humans Cytotoxic T cell heterocyclic compounds HSP90 Heat-Shock Proteins RNA Messenger Cell Proliferation Wound Healing Reverse Transcriptase Polymerase Chain Reaction Prostatic Neoplasms food and beverages Cancer medicine.disease Xenograft Model Antitumor Assays Molecular biology Oncology chemistry Cell culture Cancer cell Disease Progression Cancer research sense organs |
| Zdroj: | Cancer Prevention Research. 8:249-257 |
| ISSN: | 1940-6215 1940-6207 |
| Popis: | (−)-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. Cancer Prev Res; 8(3); 249–57. ©2015 AACR. |
| Databáze: | OpenAIRE |
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