TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells

Costantino, Elio; Maddalena, Francesca; Calise, S. John; Piscazzi, Annamaria; Tirino, Virginia; Fersini, Alberto; Ambrosi, Antonio; Neri, Vincenzo; Esposito, Franca; Landriscina, Matteo

doi:10.1016/j.canlet.2009.01.018

Cited by 121 publications

(146 citation statements)

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“…31 Interestingly, bortezomib, a reversible inhibitor of the 26S proteasome, is at present a valuable option for the first-line treatment of multiple myeloma. 32 Thus, characterization of TRAP1, a chaperone upregulated in about 60% of human CRCs, 5 as a protein involved in quality control and in protection against apoptosis in cancer cells provides a strong rationale for considering this network as a novel molecular target for treatment of human CRC.…”

Section: Resultsmentioning

confidence: 99%

“…3 Furthermore, TRAP1 showed antioxidant and antiapoptotic functions, 4 while an involvement of this mitochondrial (MITO) chaperone in the multi-drug resistance of human colorectal carcinoma (CRC) cells was also established. 5 Little is known about TRAP1 signal transduction: the first most important finding on TRAP1 function came from studies by the Altieri's group, which identified TRAP1 as a member of a cytoprotective network selectively active in the mitochondria of tumor tissues. 6 The same group has recently proposed TRAP1 as a novel molecular target in localized and metastatic prostate cancer, 7 and is now involved in a promising preclinical characterization of mitochondria-targeted smallmolecule HSP90 inhibitors.…”

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confidence: 99%

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TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

et al. 2011

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Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk. Tumor necrosis factor receptor-associated protein-1 (TRAP1) was initially identified as a TNF-receptor-associated protein and is a member of the heat-shock protein-90 (HSP90) chaperone family. 1,2 Through an mRNA-differential display analysis between oxidant-adapted and control osteosarcoma cells, our group identified, among other proteins, TRAP1, whose expression was highly induced upon oxidant adaptation. 3 Furthermore, TRAP1 showed antioxidant and antiapoptotic functions, 4 while an involvement of this mitochondrial (MITO) chaperone in the multi-drug resistance of human colorectal carcinoma (CRC) cells was also established. 5 Little is known about TRAP1 signal transduction: the first most important finding on TRAP1 function came from studies by the Altieri's group, which identified TRAP1 as a member of a cytoprotective network selectively active in the mitochondria of tumor tissues. 6 The same group has recently proposed TRAP1 as a novel molecular target in localized and metastatic prostate cancer, 7 and is now involved in a promising preclinical characterization of mitochondria-targeted smallmolecule HSP90 inhibitors. 8,9 Besides some well-characterized TRAP1 functions in mitochondria, during preparation of this manuscript it was reported that interference by HSP90 chaperones triggers an unfolded protein response (UPR) and activates autophagy in the mitochondria of tumor cells. 10 A put...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

et al. 2011

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“…Although TRAP1 is reported to be up-regulated in some cancers, its expression is diminished in others (8,(37)(38)(39). The impact of reduced TRAP1 expression on in vitro cell invasion raises the possibility that certain more aggressive, metastatic, or late-stage cancers may express less TRAP1 than less advanced tumors.…”

Section: Trap1 Expression Correlates Inversely With Tumor Stage In Cementioning

confidence: 99%

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.

235

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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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“…TRAP1 over-expression can be one of the protective mechanisms adopted during tumor progression and is closely related to the multi-drug resistance commonly found in cancer cells (24,45). Loss of the chaperone functions directly induce mitochondrial membrane permeabilization (MMP), followed by immediate cell death in many cancer cells, but not in normal cells.…”

Section: Inhibitors Targeting Mitochondrial Trap1 and Hsp90 As Cancermentioning

confidence: 99%

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

Kang¹

2012

BMB Reports

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TRAP1, a novel mitochondrial chaperone responsible for multi-drug resistance and protection from apoptotis in human colorectal carcinoma cells

Cited by 121 publications

References 26 publications

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

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

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

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