title: Polyphenon E(R), a standardized green tea extract, induces endoplasmic reticulum stress, leading to death of immortalized PNT1a cells by anoikis and tumorigenic PC3 by necroptosis.
abstract: Increasing doses of Polyphenon E®, a standardized green tea extract, were given to PNT1a and PC3 prostate epithelial cells mimicking initial and advanced stages of prostate cancer (PCa), respectively. Cell death occurred in both cell lines, with PNT1a being more sensitive [half-maximal inhibitory concentration (IC50) = 35 μg/ml] than PC3 (IC50 = 145 μg/ml) to Polyphenon E®. Cell cycle arrest occurred at G0/G1 checkpoint for PNT1a, and G2/M for PC3 cells. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) occurred in both cell lines, with each exhibiting different timing in response to Polyphenon E®. Autophagy was transiently activated in PNT1a cells within 12 h after treatment as a survival response to overcome ERS; then activation of caspases and cleavage of poly (ADP ribose) polymerase 1 occurred, committing cells to anoikis death. Polyphenon E® induced severe ERS in PC3 cells, causing a dramatic enlargement of the ER; persistent activation of UPR produced strong upregulation of GADD153/CHOP, a key protein of ERS-mediated cell death. Thereafter, GADD153/CHOP activated Puma, a BH3-only protein, committing cells to necroptosis, a programmed caspase-independent mechanism of cell death. Our results provide a foundation for the identification of novel targets and strategies aimed at sensitizing apoptosis-resistant cells to alternative death pathways.
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research and.
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Naponelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Silva
authors.forename: Alice
authors.initials: A
authors.lastname: Modernelli
authors.forename: Ileana
authors.initials: I
authors.lastname: Ramazzina
authors.forename: Martina
authors.initials: M
authors.lastname: Bonacini
authors.forename: Saverio
authors.initials: S
authors.lastname: Tardito
authors.forename: Rita
authors.initials: R
authors.lastname: Gatti
authors.forename: Jacopo
authors.initials: J
authors.lastname: Uggeri
authors.forename: Saverio
authors.initials: S
authors.lastname: Bettuzzi
mesh_terms: D023102:Anoikis / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans
chemical_list: D017931:DNA Primers; D002392:Catechin; C472086:polyphenon E