TRAP1 revisited: Novel localizations and functions of a ‘next-generation’ biomarker (Review)

Amoroso, Maria Rosaria; Matassa, Danilo Swann; Sisinni, Lorenza; Lettini, Giacomo; Landriscina, Matteo; Esposito, Franca

doi:10.3892/ijo.2014.2530

Cited by 63 publications

(72 citation statements)

References 48 publications

(56 reference statements)

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“…In agreement with a role for TRAP1 outside mitochondria, for quality control of mitochondrial proteins 46 , our findings prompted us to hypothesize that TRAP1 could possibly act as a “controller” of the correct Sho localization at the interface between the ER/mitochondrial compartments.…”

Section: Discussionsupporting

confidence: 77%

Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

Pepe

Avolio

Matassa

et al. 2017

Sci Rep

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Shadoo (Sho), a member of prion protein family, has been shown to prevent embryonic lethality in Prnp 0/0 mice and to be reduced in the brains of rodents with terminal prion diseases. Sho can also affect PrP structural dynamics and can increase the prion conversion into its misfolded isoform (PrPSc), which is amyloidogenic and strictly related to expression, intracellular localization and association of PrPC to lipid rafts. We reasoned that if Sho possesses a natural tendency to convert to amyloid-like forms in vitro, it should be able to exhibit “prion-like” properties, such as PK-resistance and aggregation state, also in live cells. We tested this hypothesis, by different approaches in neuronal cells, finding that Sho shows folding properties partially dependent on lipid rafts integrity whose alteration, as well as proteasomal block, regulated generation of intermediate Sho isoforms and exacerbated its misfolding. Moreover, a 18 kDa isoform of Sho, likely bearing the signal peptide, was targeted to mitochondria by interacting with the molecular chaperone TRAP1 which, in turn controlled Sho dual targeting to ER or mitochondria. Our studies contribute to understand the role of molecular chaperones and of PrP-related folding intermediates in “prion-like” conversion.

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Section: Discussionsupporting

confidence: 77%

Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

Pepe

Avolio

Matassa

et al. 2017

Sci Rep

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“…The therapeutic selectivity of Hsp90 inhibitors results from the presence of a high-affinity, activated form of Hsp90 in tumours, whereas the Hsp90 in normal tissues is a low-affinity, inactive form [37]. Similarly, TRAP1 has been pursued as a promising target for novel mitochondriotopic/therapeutic strategies for its cytoprotective and antiapoptotic roles in cancer cells [6] and other diseases [38], although recent advances in TRAP1 biology suggest to be prudent [25]. In this article, we have shown that TRAP1 expression also influences tumour cell's migratory potential, which raises new questions to answer in the near future in order to select TRAP1 as predictive biomarker of cancer progression and metastasis.…”

Section: Discussionmentioning

confidence: 97%

“…Recent advances in TRAP1 biology have shown how TRAP1 functions as a network hub protein, involved in all these cellular processes. In fact, TRAP1 i) contributes to the regulation of mitochondrial physiology through an interaction and regulation of respiratory complexes [3][4][5]; ii) is part of a pro-survival signalling pathway aimed at evading the toxic effects of oxidants and anticancer drugs and plays a role in protecting mitochondria against apoptotic stimuli [25]; and iii) controls protein homeostasis through a direct involvement in the regulation of protein synthesis and degradation [2,12,15]. Whether its roles in such processes are uniformly oncogenic or not is now matter of debate.…”

Section: Discussionmentioning

confidence: 99%

TRAP1 controls cell migration of cancer cells in metabolic stress conditions: Correlations with AKT/p70S6K pathways

Agliarulo

Matassa

Amoroso

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Cell motility is a highly dynamic phenomenon that is essential to physiological processes such as morphogenesis, wound healing and immune response, but also involved in pathological conditions such as metastatic dissemination of cancers. The involvement of the molecular chaperone TRAP1 in the regulation of cell motility, although still controversial, has been recently investigated along with some well-characterized roles in cancer cell survival and drug resistance in several tumour types. Among different functions, TRAP1-dependent regulation of protein synthesis seems to be involved in the migratory behaviour of cancer cells and, interestingly, the expression of p70S6K, a kinase responsible for translation initiation, playing a role in cell motility, is regulated by TRAP1. In this study, we demonstrate that TRAP1 silencing enhances cell motility in vitro but compromises the ability of cells to overcome stress conditions, and that this effect is mediated by the AKT/p70S6K pathway. In fact: i) inhibition of p70S6K activity specifically reduces migration in TRAP1 knock-down cells; ii) nutrient deprivation affects p70S6K activity thereby impairing cell migration only in TRAP1-deficient cells; iii) TRAP1 regulates the expression of both AKT and p70S6K at post-transcriptional level; and iii) TRAP1 silencing modulates the expression of genes involved in cell motility and epithelial-mesenchymal transition. Notably, a correlation between TRAP1 and AKT expression is found in vivo in human colorectal tumours. These results provide new insights into TRAP1 role in the regulation of cell migration in cancer cells, tumour progression and metastatic mechanisms.

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“…TRAP1 is a HSP90 molecular chaperone upregulated in several human malignancies [5, 6] and, among others, human CRC [7]. High TRAP1 levels have been proposed as prognostic biomarker in this malignancy, being associated with extensive lymph node dissemination [8] and, together with high ERCC1, with poor overall survival (OS) in metastatic disease [9].…”

Section: Introductionmentioning

confidence: 99%

“…TRAP1 regulation of these cell functions depends on the co-translational quality control of specific client proteins and, thus, the modulation of the expression/ubiquitination of a network of proteins [11, 12]. In such a context, we previously suggested that human CRCs with increased TRAP1 expression are characterized by selective upregulation of specific TRAP1 network proteins [6, 13, 20, 21], even though the clinical significance of this regulation is still largely unexplored [6]. Thus, this study was designed to obtain a comprehensive evaluation of the biological and clinical relevance of TRAP1 protein network in human CRC and to address the hypothesis that the coordinated upregulation of TRAP1 and its client proteins may serve as a prognostic signature in metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

et al. 2017

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TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors. TRAP1 is upregulated at the transition between low-and high-grade adenomas, in in situ carcinomas and in about 60% of human colorectal carcinomas, being downregulated only in a small cohort of tumors. The analysis of TCGA database showed that a subgroup of colorectal tumors is characterized by gain/loss of TRAP1 copy number, this correlating with its mRNA and protein expression. Interestingly, TRAP1 is co-expressed with the majority of its client proteins and hierarchical cluster analysis showed that the upregulation of TRAP1 and associated 6-protein signature (i.e., IF2α, eF1A, TBP7, MAD2, CDK1 and βCatenin) identifies a cohort of metastatic colorectal carcinomas with a significantly shorter overall survival (HR 5.4; 95% C.I. 1.1-26.6; p=0.037). Consistently, the prognostic relevance of TRAP1 was confirmed in a cohort of 55 metastatic colorectal tumors. Finally, TRAP1 positive expression and its prognostic value are more evident in left colon cancers. These data suggest that TRAP1 protein network may provide a prognostic signature in human metastatic colorectal carcinomas.

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TRAP1 revisited: Novel localizations and functions of a ‘next-generation’ biomarker (Review)

Cited by 63 publications

References 48 publications

Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

Regulation of sub-compartmental targeting and folding properties of the Prion-like protein Shadoo

TRAP1 controls cell migration of cancer cells in metabolic stress conditions: Correlations with AKT/p70S6K pathways

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

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