Chronic administration of green tea extract to TRAMP mice induces the collapse of Golgi apparatus in prostate secretory cells and results in alterations of protein post-translational processing

Abstract

Abstract. Considering its long latency, prostate cancer (PCa) represents an ideal target for chemoprevention strategies. Green tea extract (GTE) has been proved to be one of the most promising natural substances capable of inhibiting PCa progression in animal models (transgenic adenocarcinoma of mouse prostate), as well as in humans. However, the cellular targets of the GTE action are mostly unknown. The main objective of this work was to investigate whether the endoplasmic reticulum (ER) and the Golgi apparatus (GA), known to be actively involved in sensing stress stimuli and initiating and propagating cell death signalling, may represent the subcellular targets of GTE action. To this end, 42 TRAMP mice were divided into four experimental groups: groups II and IV, received GTE in tap water (0.3 g/100 ml solution) starting at 8 weeks of age and up to the time of sacrifice. Groups I and III were respective agematched water-fed controls. The animals were sacrificed after 4 weeks (groups I and II) or 40 weeks of treatment (groups II and IV). We also treated TRAMP-C2 cells with GTE (20 µg/ml for 7 days) to check the expression profile of clusterin (CLU), a protein involved in prostate tumourigenesis, extensively processed through ER-GA before being secreted through the plasma membrane. In vivo we found that chronic administration of GTE in TRAMP mice results in collapse of ER and GA in prostate epithelial cells. Consistently, in vitro we found that the mature, fully processed form of CLU, sCLU, is strongly reduced by GTE treatment in TRAMP-C2 cells. Taking into account the sCLU biogenesis dependence on the ER-GA integrity and the proposed anti-apoptotic role of sCLU, the possibility for GTE to counteract PCa progression by interfering with sCLU biogenesis is suggested.

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

“…No effects were observed in age matched animals that were water fed. In agreement with morphological data, we found that the biogenesis of secreted proteins is altered in TRAMP-C2 cells treated with 20 µg/mL of GTCs [136]. We reported that autophagy was transiently activated in human prostate PNT1a cells, commonly used to mimic the initial stages of PCa, as a survival response to overcome Polyphenon E ® -induced ER stress [42].…”

Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds

“…A GTE extract, Polyphenon E ® , caused severe and prolonged ER stress in human prostate cancer cells PC3 by activating the PERK signaling arm, as demonstrated by prolonged activation of p-eIF2α and ATF4 [83]. A significant activation of XBP1 mRNA splicing has also been observed in these cells, indicating an involvement of both IRE1α and ATF6 signaling arms of ER stress in the cellular response to Polyphenon E ® [84].…”

EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism

“…Proteasome inhibition is one of the mechanisms underlying the anticancer properties of EGCG 20 21 22 . Moreover, green tea extracts dramatically reduce the glycosylation capacity of ER, impacting the post-translational mechanism of protein maturation in vivo and in vitro 23 . 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 .…”