Abstract
The proteasome inhibitors Bortezomib (BZM) and MG132 trigger cancer cell death via induction of endoplasmic reticulum (ER) stress and unfolded protein response. Epigallocatechin gallate (EGCG), the most bioactive green tea polyphenol, is known to display strong anticancer properties as it inhibits proteasome activity and induces ER stress. We investigated whether combined delivery of a proteasome inhibitor with EGCG enhances prostate cancer cell death through increased induction of ER stress. Paradoxically, EGCG antagonized BZM cytotoxicity even when used at low concentrations. Conversely, the MG132 dose-response curve was unaffected by co-administration of EGCG. Moreover, apoptosis, proteasome inhibition and ER stress were inhibited in PC3 cells simultaneously treated with BZM and EGCG but not with a combination of MG132 and EGCG; EGCG enhanced autophagy induction in BZM-treated cells only. Autophagy inhibition restored cytotoxicity concomitantly with CHOP and p-eIF2α up-regulation in cells treated with BZM and EGCG. Overall, these findings demonstrate that EGCG antagonizes BZM toxicity by exacerbating the activation of autophagy, which in turn mitigates ER stress and reduces CHOP up-regulation, finally protecting PC3 cells from cell death.
Highlights
Tumor growth in prostate adenocarcinoma (PCa) animal models[3,5,6]
Cell death triggered by proteasome inhibitors is associated with induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), inhibition of the nuclear factor kappa B (NF-kB) inflammatory pathway, activation of caspase-8 and apoptosis, and increased generation of reactive oxygen species (ROS)[10,11]
Recent studies indicate that cell death induced by BZM and MG132 is a consequence of the accumulation of unfolded/damaged proteins culminating in activation of the ER stress response (ESR)[12,13]
Summary
Tumor growth in PCa animal models[3,5,6]. MG132 (N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal) is a peptide aldehyde-based molecule that binds covalently to the active site of the beta subunits of 20S proteasome, leading to effective inhibition of 26S proteasome complex activity[7]. Cell death triggered by proteasome inhibitors is associated with induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), inhibition of the nuclear factor kappa B (NF-kB) inflammatory pathway, activation of caspase-8 and apoptosis, and increased generation of reactive oxygen species (ROS)[10,11]. Polyphenon E , a standardized green tea extract mainly composed of EGCG (65%), exerts its antitumor effect on PCa cells by inducing ER stress, which in turn activates UPR associated signals[24]. Other Authors reported that BZM potentiates EGCG-mediated myeloma cell growth inhibition and apoptosis induction[27] Besides these contradicting findings in multiple myeloma cells, it is noteworthy to mention that no antagonistic interaction between BZM and EGCG occurred in vivo, when a preclinical PCa model was used[28]. We investigated the impact of these combinations on molecular mechanisms involved in the control of protein homeostasis, induction of stress response and commitment to cell death
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