title: Modulation of CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 expression by nelfinavir sensitizes glioblastoma multiforme cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
abstract: Human glioblastoma multiforme cells demonstrate varying levels of sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Endoplasmic reticulum (ER) stress has been shown to trigger cell death through apoptosis. We therefore pursued a strategy of integrating clinically relevant investigational agents that cooperate mechanistically through the regulation of ER stress and apoptosis pathways. Nelfinavir belongs to the protease inhibitor class of drugs currently used to treat patients with HIV and is in clinical trials as an anti-tumor agent. We found that Nelfinavir treatment led to ER stress-induced up-regulation of the DR5 receptor. This transactivation was mediated by the transcription factor CCAAT/enhancer binding protein homologous protein (CHOP). We also determined that ER stress-induced ATF4 up-regulation was responsible for modulation of CHOP. In contrast, DR4 receptor expression was unchanged by Nelfinavir treatment. Combining Nelfinavir with TRAIL led to a significantly enhanced level of apoptosis that was abrogated by siRNA silencing of DR5. We provide evidence that Nelfinavir-induced ER stress modulates DR5 expression in human glioblastoma multiforme cells and can enhance TRAIL efficacy. These studies provide a potential mechanistic rationale for the use of the Food and Drug Administration-approved agent Nelfinavir in combination with DR5 agonists to induce apoptosis in human malignancies.
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Michelle
authors.initials: M
authors.lastname: Alonso-Basanta
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hahn
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.affiliation: Department of Radiation Oncology and the Radiation Biology and Imaging Program of the Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. Electronic address: JayD@uphs.upenn.edu.
authors.forename: Jay F
authors.initials: JF
authors.lastname: Dorsey
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; C497249:DDIT3 protein, human; D017320:HIV Protease Inhibitors; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019888:Nelfinavir