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 anti-cancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We utilized non-tumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer (PRCA) 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 (NB), 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 PRCA 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 to NT cells and binding occurred through the HSP90 C-terminus. Additionally, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, NB, 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 PRCA because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype.

Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation

“…Hsp90 is commonly overexpressed in cancer cells and stabilizes many clients known to promote oncogenesis, including transcription factors, signaling proteins and kinases [9,16]. Multiple studies have shown that certain tumor cells are more dependent on Hsp90 activity compared to non-malignant cells [17–19].…”

Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas

“…HSP90 also participates in regulation of gene expression and genome maintenance (Fang et al 2014); (Sollars et al 2003;Lu et al 2012a, b). Despite these uncertainties, the observation that H90Ins as a class concentrate in tumor cells to a greater degree than in normal tissue is of importance and a point of hope (Kamal et al 2003); (Moulick et al 2011); (Taldone et al 2014); (Suzuki et al 2015); (Moses et al 2015). The notion that rapidly proliferating malignant cells in a toxic microenvironment have a larger population of targetable molecular chaperones such as HSP90, and depend more on these proteostasis components for survival, fits well with the concept of chaperone addiction put forth by many others in the field (Miyata et al 2013); (Prodromou 2009); (Workman et al 2007a); (Calderwood et al 2006); (Xiao et al 2007); ( Barrott and Haystead 2013).…”

Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

“…EGCG, with Hsp90 inhibition, showed a protective effect against cancer in a novel human prostate cancer progression model [58]. In primary vascular endothelial cells, GST and NQO1 enzymes were increased dose-dependently by Nrf2 [59].…”