title: Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis.
abstract: TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshida
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Guillaume
authors.initials: G
authors.lastname: Muhlebach
authors.forename: Carole
authors.initials: C
authors.lastname: Sourbier
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.forename: Evangelia
authors.initials: E
authors.lastname: Vartholomaiou
authors.forename: Manabu
authors.initials: M
authors.lastname: Tatokoro
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Naoto
authors.initials: N
authors.lastname: Miyajima
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.forename: Wanping
authors.initials: W
authors.lastname: Xu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukushima
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Koga
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kihara
authors.forename: Jane
authors.initials: J
authors.lastname: Trepel
authors.forename: Didier
authors.initials: D
authors.lastname: Picard
authors.forename: Leonard
authors.initials: L
authors.lastname: Neckers
mesh_terms: D000818:Animals; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002522:Chlorocebus aethiops; D006019:Glycolysis; D018841:HSP90 Heat-Shock Proteins; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics; D010085:Oxidative Phosphorylation; D034622:RNA Interference; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C547760:TRAP-1 protein, mouse; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
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