title: Exploiting the mitochondrial unfolded  protein response for cancer therapy  in mice and human cells.
abstract: Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.
authors.affiliation: Prostate Cancer Discovery and Development Program, Philadelphia, Pennsylvania, USA.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
authors.forename: Takehiko
authors.initials: T
authors.lastname: Dohi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Raskett
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Orlowski
authors.forename: Christine M
authors.initials: CM
authors.lastname: Powers
authors.forename: Candace A
authors.initials: CA
authors.lastname: Gilbert
authors.forename: Alonzo H
authors.initials: AH
authors.lastname: Ross
authors.forename: Janet
authors.initials: J
authors.lastname: Plescia
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D056811:Unfolded Protein Response
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006146:Guanidines; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C557898:gamitrinib-G4