title: Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s.
abstract: Tumors successfully adapt to constantly changing intra- and extracellular environments, but the wirings of this process are still largely elusive. Here, we show that heat-shock-protein-90-directed protein folding in mitochondria, but not cytosol, maintains energy production in tumor cells. Interference with this process activates a signaling network that involves phosphorylation of nutrient-sensing AMP-activated kinase, inhibition of rapamycin-sensitive mTOR complex 1, induction of autophagy, and expression of an endoplasmic reticulum unfolded protein response. This signaling network confers a survival and proliferative advantage to genetically disparate tumors, and correlates with worse outcome in lung cancer patients. Therefore, mitochondrial heat shock protein 90s are adaptive regulators of tumor bioenergetics and tractable targets for cancer therapy.
authors.affiliation: Prostate Cancer Discovery and Development Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Young Chan
authors.initials: YC
authors.lastname: Chae
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Caino
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.forename: Jagadish C
authors.initials: JC
authors.lastname: Ghosh
authors.forename: Takehiko
authors.initials: T
authors.lastname: Dohi
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.forename: Luigi
authors.initials: L
authors.lastname: Santambrogio
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004734:Energy Metabolism; D006146:Guanidines / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D056811:Unfolded Protein Response
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006146:Guanidines; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C509805:KIF2A protein, human; D047029:Lactams, Macrocyclic; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; C557898:gamitrinib-G4; D000076222:Mechanistic Target of Rapamycin Complex 1; C526183:PRKAB2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D016547:Kinesins