title: EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism.
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.
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Modernelli
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.|Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy.|National Institute of Biostructure and Biosystems (INBB), Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Naponelli
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Giovanna Troglio
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Bonacini
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.|Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy.|National Institute of Biostructure and Biosystems (INBB), Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Ramazzina
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.|Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy.|National Institute of Biostructure and Biosystems (INBB), Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bettuzzi
authors.affiliation: Department of Biomedicine, Biotechnology and Translational Research, University of Parma, Via Volturno 39/a, 43125 Parma, Italy.|Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy.|National Institute of Biostructure and Biosystems (INBB), Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000069286:Bortezomib / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D015852:Eukaryotic Initiation Factor-2; D007976:Leupeptins; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D002392:Catechin; C045651:epigallocatechin gallate; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde