Control of Tumor Bioenergetics and Survival Stress Signaling by Mitochondrial HSP90s

Chae, Young Chan; Caino, M. Cecilia; Lisanti, Sofia; Ghosh, Jagadish C.; Dohi, Takehiko; Danial, Nika N.; Villanueva, Jessie; Ferrero, Stefano; Vaira, Valentina; Santambrogio, Luigi; Bòsari, Silvano; Languino, Lucia R.; Herlyn, Meenhard; Altieri, Dario C.

doi:10.1016/j.ccr.2012.07.015

Cited by 106 publications

(144 citation statements)

References 40 publications

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“…Aerobic glycolysis is suppressed as a byproduct of this altered metabolic landscape, likely because of, in part, allosteric inhibition of the glycolytic enzyme phosphofructokinase. These data are in general agreement with a recent study showing that TRAP1 silencing in a glioblastoma cell line resulted in a variety of metabolic changes suggestive of reduced glycolysis, including reduced lactic acid secretion (44). Suppression of glycolysis concomitant with enhanced fatty acid oxidation and increased steady-state levels of several TCA cycle intermediates, including oxaloacetate, strongly suggest that TRAP1-deficient cells use one or more anaplerotic mechanisms to sustain their mitochondrial metabolism.…”

Section: Discussionsupporting

confidence: 81%

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

223

272

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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.M olecular chaperones help to maintain cellular homeostasis.The heat-shock protein 90 (HSP90) family of molecular chaperones is highly conserved from bacteria to mammals. HSP90 itself is an essential molecular chaperone found in the cytoplasm and nucleus of all eukaryotic cells (1, 2). In multicellular eukaryotes, the HSP90 family includes the mitochondrial chaperone TRAP1 (TNF receptor-associated protein), which shares 50% sequence similarity with HSP90. Although TRAP1 binds and hydrolyzes ATP in an analogous manner to HSP90 (3), its cellular function is less well understood. Thus, although many HSP90-dependent proteins ("clients") and interacting cochaperones have been described (www.picard.ch/downloads/Hsp90interactors.pdf), the validated list of TRAP1-dependent clients is quite small and TRAP1-interacting cochaperones, if they exist, have yet to be identified (4).Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5, 6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8, 9), may contribute to its antiapoptotic activity (4). For these reasons, TRAP1 has been proposed as an anticancer molecular target, and first-generation inhibitors have shown some anticancer activity in preclinical models (10). However, these inhibitors do not distinguish between HSP90 and TRAP1 (11), and TRAP1 expression in cancer is variable but HSP90 comprises as much as 5% of...

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Section: Discussionsupporting

confidence: 81%

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

223

272

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“…In these experiments, noncytotoxic concentrations of Gamitrinib (23) suppressed the migration ( Figure 1A and Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/JCI67841DS1), and invasion ( Figure 1B and Supplemental Figure 1B) of tumor cell types. When tested in a more physiologic 3D model of cellular motility, Gamitrinib blocked tumor cell invasion in organotypic spheroids embedded in a collagen matrix ( Figure 1C), with nearly complete suppression of invasive length and invasive areas ( Figure 1D).…”

Section: Mitochondrial Hsp90 Regulation Of Tumor Cell Motilitymentioning

confidence: 99%

“…In addition to opposing CypD-dependent permeability transition (21), mitochondrial Hsp90s maintain ATP production in tumor cells via retention of HK-II to the organelle outer membrane (23). To test whether this function in bioenergetics was important for tumor cell motility, we next treated tumor cells with the mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and looked for changes in cell motility.…”

Section: Mitochondrial Hsp90 Regulation Of Tumor Cell Motilitymentioning

confidence: 99%

“…We focused on a network of heat shock protein-90 (Hsp90) chaperones (20) that is preferentially, if not exclusively, found in mitochondria of tumor cells (21). Functionally, these molecules oversee the organelle protein folding environment in tumors, antagonizing cyclophilin D-dependent (CypD-dependent) permeability transition (22), and maintaining energy production via retention of the glycolytic enzyme, hexokinase II, to the mitochondrial outer membrane (23).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

et al. 2013

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Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non-small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.

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“…It can therefore be reasonably deduced that Hsp90 takes part in trafficking of Tom40 to the mitochondrial membrane. Interestingly, a significant role of the mitochondrial Hsp90 in keeping energy production in cancer cells has been observed recently [25,26]. In can be, therefore, assumed that blocking Hsp90 activity results in mitochondrial disruption and metabolic changes, however, the exact mechanism depends on the drug used and the part of Hsp90 affected.…”

Section: Metabolomic Analysis Of Cell Pellets (A) and Media (B-d) 4 mentioning

confidence: 99%

Hsp90 Inhibition Affects Cell Metabolism by Disrupting Mitochondrial Protein Insertion

Mycielska¹,

Wachsmuth²,

Dettmer³

et al. 2014

CBCM

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Control of Tumor Bioenergetics and Survival Stress Signaling by Mitochondrial HSP90s

Cited by 106 publications

References 40 publications

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

Hsp90 Inhibition Affects Cell Metabolism by Disrupting Mitochondrial Protein Insertion

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