title: Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress.
abstract: Tunicamycin (TUN), an inhibitor of protein glycosylation and therefore a potent stimulator of endoplasmic reticulum (ER) stress, has been used to improve anticancer drug efficacy, but the underlying mechanism remains obscure. In this study, we show that acute administration of TUN in mice induces the unfolded protein response and suppresses the levels of P21, a cell cycle regulator with anti-apoptotic activity. The inhibition of P21 after ER stress appears to be C/EBP homologous protein (CHOP)-dependent because in CHOP-deficient mice, TUN not only failed to suppress, but rather induced the expression of P21. Results of promoter-activity reporter assays using human cancer cells and mouse fibroblasts indicated that the regulation of P21 by CHOP operates at the level of transcription and involves direct binding of CHOP transcription factor to the P21 promoter. The results of cell viability and clonogenic assays indicate that ER-stress-related suppression of P21 expression potentiates caspase activation and sensitizes cells to doxorubicin treatment, while administration of TUN to mice increases the therapeutic efficacy of anticancer therapy for HepG2 liver and A549 lung cancers.
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Chrysovalantou
authors: C
authors: Mihailidou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Ioulia
authors: I
authors: Chatzistamou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA.
authors: Athanasios G
authors: AG
authors: Papavassiliou
authors: Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA Department of Biological ChemistryUniversity of Athens Medical School, Athens 11527, GreeceDepartment of Basic SciencesDental School, University of Athens, Athens 11527, GreeceDepartment of PathologyMicrobiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USADepartment of Drug Discovery and Biomedical SciencesUniversity of South Carolina, Columbia, South Carolina 29425, USA kiarish@sccp.sc.edu.
authors: Hippokratis
authors: H
authors: Kiaris
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology / Q000627:therapeutic use; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497250:Ddit3 protein, mouse; D016159:Tumor Suppressor Protein p53; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D004317:Doxorubicin
keywords: chaperone; chemotherapy; therapy; unfolded protein response