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Matteo Landriscina - One of the best experts on this subject based on the ideXlab platform.
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TRAP1 regulates wnt β catenin pathway through lrp5 6 receptors expression modulation
International Journal of Molecular Sciences, 2020Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Michele Pietrafesa, Fabiana Crispo, Pietro Zoppoli, Ilaria Laurenzana, Alessandro Sgambato, Matteo LandriscinaAbstract:Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
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TRAP1 regulation of cancer metabolism dual role as oncogene or tumor suppressor
Genes, 2018Co-Authors: Danilo Swann Matassa, Matteo Landriscina, Ilenia Agliarulo, Rosario Avolio, Franca EspositoAbstract:Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.
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TRAP1 a viable therapeutic target for future cancer treatments
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Matteo LandriscinaAbstract:ABSTRACTIntroduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.Expert opinion: TRAP1 targeting may represent a promising stra...
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TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial mesenchymal transition
Cell Death and Disease, 2016Co-Authors: Maria Rosaria Amoroso, Matteo Landriscina, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Ilenia Agliarulo, Rosario Avolio, Hani Gabra, Franca EspositoAbstract:Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC. At molecular level, downregulation of TRAP1 associates with higher expression of p70S6K, a kinase frequently active in OC with emerging roles in cell migration and tumor metastasis. Indeed, TRAP1 silencing in different OC cells induces upregulation of p70S6K expression and activity, enhancement of cell motility and epithelial–mesenchymal transition (EMT). Consistently, in a large cohort of OC patients, TRAP1 expression is reduced in tumor metastases and directly correlates with the epithelial marker E-Cadherin, whereas it inversely correlates with the transcription factor Slug and the matrix metallopeptidases 2 and 9. Strikingly, pharmacological inhibition of p70S6K reverts the high motility phenotype of TRAP1 knock-down cells. However, although p70S6K inhibition or silencing reduces the expression of the transcription factors Snail and Slug, thus inducing upregulation of E-Cadherin expression, it is unable to revert EMT induced by TRAP1 silencing; furthermore, p70S6K did not show any significant correlation with EMT genes in patients, nor with overall survival or tumor stage, suggesting an independent and predominant role for TRAP1 in OC progression. Altogether, these results may provide novel approaches in OC with reduced TRAP1 expression, which could be resistant to therapeutic strategies based on the inhibition of the p70S6K pathway, with potential future intervention in OC invasion and metastasis.
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targeting TRAP1 as a downstream effector of braf cytoprotective pathway a novel strategy for human braf driven colorectal carcinoma
Oncotarget, 2015Co-Authors: Valentina Condelli, Francesca Maddalena, Maria Rosaria Amoroso, Annamaria Piscazzi, Franca Esposito, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Giuseppe Palladino, Matteo LandriscinaAbstract:// Valentina Condelli 1, * , Francesca Maddalena 1, * , Lorenza Sisinni 1 , Giacomo Lettini 1 , Danilo Swann Matassa 2 , Annamaria Piscazzi 3 , Giuseppe Palladino 3 , Maria Rosaria Amoroso 2 , Franca Esposito 2 , Matteo Landriscina 3 1 Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy 2 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy 3 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy * These authors have contributed equally to this work Correspondence to: Matteo Landriscina, e-mail: matteo.landriscina@unifg.it Franca Esposito, e-mail: franca.esposito@unina.it Keywords: BRAF, TRAP1, apoptosis, colon cancer, drug resistance Received: April 13, 2015 Accepted: June 01, 2015 Published: June 13, 2015 ABSTRACT The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination, since BRAF down-regulation, ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition. Since TRAP1 is upregulated in human colorectal carcinomas (CRCs) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies, the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated. This study reports that BRAF cytoprotective signaling involves TRAP1-dependent inhibition of the mitochondrial apoptotic pathway. It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation, a condition associated with resistance to apoptosis. Consistently, a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug-resistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells. Thus, TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells.
Francesca Maddalena - One of the best experts on this subject based on the ideXlab platform.
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TRAP1 enhances warburg metabolism through modulation of pfk1 expression activity and favors resistance to egfr inhibitors in human colorectal carcinomas
Molecular Oncology, 2020Co-Authors: Francesca Maddalena, Valentina Condelli, Danilo Swann Matassa, Giacomo Lettini, Valeria Li Bergolis, Consiglia Pacelli, Rosella Scrima, Michele Pietrafesa, Fabiana Crispo, Annamaria PiscazziAbstract:Metabolic rewiring is a mechanism of adaptation to unfavorable environmental conditions and tumor progression. TRAP1 is an HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for downregulation of oxidative phosphorylation (OXPHOS) and adaptation to metabolic stress. The mechanism by which TRAP1 regulates glycolytic metabolism and the relevance of this regulation in resistance to EGFR inhibitors were investigated in patient-derived CRC spheres, human CRC cells, samples, and patients. A linear correlation was observed between TRAP1 levels and 18 F-fluoro-2-deoxy-glucose (18 F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake, and lactate production and downregulates OXPHOS in CRC patient-derived spheroids and cell lines. Mechanistically, TRAP1 maximizes lactate production to balance low OXPHOS through the regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); this depends on the interaction between TRAP1 and PFK1, which favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. By contrast, TRAP1/PFK1 interaction is lost in conditions of enhanced OXPHOS, which results in loss of TRAP1 regulation of PFK1 activity and lactate production. Notably, TRAP1 regulation of glycolysis is involved in resistance of RAS-wild-type CRCs to EGFR monoclonals. Indeed, either TRAP1 upregulation or high glycolytic metabolism impairs cetuximab activity in vitro, whereas TRAP1 targeting and/or inhibition of glycolytic pathway enhances cell response to cetuximab. Finally, a linear correlation between 18 F-FDG PET uptake and poor response to cetuximab in first-line therapy in human metastatic CRCs was observed. These results suggest that TRAP1 is a key determinant of CRC metabolic rewiring and favors resistance to EGFR inhibitors through regulation of glycolytic metabolism.
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TRAP1 regulates wnt β catenin pathway through lrp5 6 receptors expression modulation
International Journal of Molecular Sciences, 2020Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Michele Pietrafesa, Fabiana Crispo, Pietro Zoppoli, Ilaria Laurenzana, Alessandro Sgambato, Matteo LandriscinaAbstract:Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
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TRAP1 controls cell cycle g2 m transition through the regulation of cdk1 and mad2 expression ubiquitination
The Journal of Pathology, 2017Co-Authors: Lorenza Sisinni, Francesca Maddalena, Annamaria Piscazzi, Valentina Condelli, Danilo Swann Matassa, Vittorio Simeon, Giuseppe Pannone, Valeria Li Bergolis, Elvira Lopes, Carmela MazzoccoliAbstract:Regulation of tumour cell proliferation by molecular chaperones is still a complex issue. Here, the role of the HSP90 molecular chaperone TRAP1 in cell cycle regulation was investigated in a wide range of human breast, colorectal, and lung carcinoma cell lines, and tumour specimens. TRAP1 modulates the expression and/or the ubiquitination of key cell cycle regulators through a dual mechanism: (i) transcriptional regulation of CDK1, CYCLIN B1, and MAD2, as suggested by gene expression profiling of TRAP1-silenced breast carcinoma cells; and (ii) post-transcriptional quality control of CDK1 and MAD2, being the ubiquitination of these two proteins enhanced upon TRAP1 down-regulation. Mechanistically, TRAP1 quality control on CDK1 is crucial for its regulation of mitotic entry, since TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with the proteasome regulatory particle TBP7, this representing the limiting factor in TRAP1 regulation of the G2-M transition. Indeed, TRAP1 silencing results in enhanced CDK1 ubiquitination, lack of nuclear translocation of CDK1/cyclin B1 complex, and increased MAD2 degradation, whereas CDK1 forced up-regulation partially rescues low cyclin B1 and MAD2 levels and G2-M transit in a TRAP1-poor background. Consistently, the CDK1 inhibitor RO-3306 is less active in a TRAP1-high background. Finally, a significant correlation was observed between TRAP1 and Ki67, CDK1 and/or MAD2 expression in breast, colorectal, and lung human tumour specimens. This study represents the first evidence that TRAP1 is relevant in the control of the complex machinery that governs cell cycle progression and mitotic entry and provides a strong rationale to regard TRAP1 as a biomarker to select tumours with deregulated cell cycle progression and thus likely poorly responsive to novel cell cycle inhibitors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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TRAP1 a viable therapeutic target for future cancer treatments
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Matteo LandriscinaAbstract:ABSTRACTIntroduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.Expert opinion: TRAP1 targeting may represent a promising stra...
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TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma
Oncotarget, 2017Co-Authors: Francesca Maddalena, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Vittorio Simeon, Giulia Vita, Annamaria Bochicchio, Luciana Possidente, Valeria Li BergolisAbstract:// Francesca Maddalena 1 , Vittorio Simeon 1 , Giulia Vita 2 , Annamaria Bochicchio 3 , Luciana Possidente 2 , Lorenza Sisinni 1 , Giacomo Lettini 1 , Valentina Condelli 1 , Danilo Swann Matassa 4 , Valeria Li Bergolis 5 , Alberto Fersini 6 , Sante Romito 5 , Michele Aieta 3 , Antonio Ambrosi 6 , Franca Esposito 4 , Matteo Landriscina 1, 5 1 Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 2 Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 3 Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy 6 General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy Correspondence to: Matteo Landriscina, email: matteo.landriscina@unifg.it Franca Esposito, email: franca.esposito@unina.it Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival Received: November 02, 2016 Accepted: January 09, 2017 Published: February 03, 2017 ABSTRACT 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.
Danilo Swann Matassa - One of the best experts on this subject based on the ideXlab platform.
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TRAP1 enhances warburg metabolism through modulation of pfk1 expression activity and favors resistance to egfr inhibitors in human colorectal carcinomas
Molecular Oncology, 2020Co-Authors: Francesca Maddalena, Valentina Condelli, Danilo Swann Matassa, Giacomo Lettini, Valeria Li Bergolis, Consiglia Pacelli, Rosella Scrima, Michele Pietrafesa, Fabiana Crispo, Annamaria PiscazziAbstract:Metabolic rewiring is a mechanism of adaptation to unfavorable environmental conditions and tumor progression. TRAP1 is an HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for downregulation of oxidative phosphorylation (OXPHOS) and adaptation to metabolic stress. The mechanism by which TRAP1 regulates glycolytic metabolism and the relevance of this regulation in resistance to EGFR inhibitors were investigated in patient-derived CRC spheres, human CRC cells, samples, and patients. A linear correlation was observed between TRAP1 levels and 18 F-fluoro-2-deoxy-glucose (18 F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake, and lactate production and downregulates OXPHOS in CRC patient-derived spheroids and cell lines. Mechanistically, TRAP1 maximizes lactate production to balance low OXPHOS through the regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); this depends on the interaction between TRAP1 and PFK1, which favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. By contrast, TRAP1/PFK1 interaction is lost in conditions of enhanced OXPHOS, which results in loss of TRAP1 regulation of PFK1 activity and lactate production. Notably, TRAP1 regulation of glycolysis is involved in resistance of RAS-wild-type CRCs to EGFR monoclonals. Indeed, either TRAP1 upregulation or high glycolytic metabolism impairs cetuximab activity in vitro, whereas TRAP1 targeting and/or inhibition of glycolytic pathway enhances cell response to cetuximab. Finally, a linear correlation between 18 F-FDG PET uptake and poor response to cetuximab in first-line therapy in human metastatic CRCs was observed. These results suggest that TRAP1 is a key determinant of CRC metabolic rewiring and favors resistance to EGFR inhibitors through regulation of glycolytic metabolism.
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TRAP1 regulation of cancer metabolism dual role as oncogene or tumor suppressor
Genes, 2018Co-Authors: Danilo Swann Matassa, Matteo Landriscina, Ilenia Agliarulo, Rosario Avolio, Franca EspositoAbstract:Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.
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TRAP1 controls cell cycle g2 m transition through the regulation of cdk1 and mad2 expression ubiquitination
The Journal of Pathology, 2017Co-Authors: Lorenza Sisinni, Francesca Maddalena, Annamaria Piscazzi, Valentina Condelli, Danilo Swann Matassa, Vittorio Simeon, Giuseppe Pannone, Valeria Li Bergolis, Elvira Lopes, Carmela MazzoccoliAbstract:Regulation of tumour cell proliferation by molecular chaperones is still a complex issue. Here, the role of the HSP90 molecular chaperone TRAP1 in cell cycle regulation was investigated in a wide range of human breast, colorectal, and lung carcinoma cell lines, and tumour specimens. TRAP1 modulates the expression and/or the ubiquitination of key cell cycle regulators through a dual mechanism: (i) transcriptional regulation of CDK1, CYCLIN B1, and MAD2, as suggested by gene expression profiling of TRAP1-silenced breast carcinoma cells; and (ii) post-transcriptional quality control of CDK1 and MAD2, being the ubiquitination of these two proteins enhanced upon TRAP1 down-regulation. Mechanistically, TRAP1 quality control on CDK1 is crucial for its regulation of mitotic entry, since TRAP1 interacts with CDK1 and prevents CDK1 ubiquitination in cooperation with the proteasome regulatory particle TBP7, this representing the limiting factor in TRAP1 regulation of the G2-M transition. Indeed, TRAP1 silencing results in enhanced CDK1 ubiquitination, lack of nuclear translocation of CDK1/cyclin B1 complex, and increased MAD2 degradation, whereas CDK1 forced up-regulation partially rescues low cyclin B1 and MAD2 levels and G2-M transit in a TRAP1-poor background. Consistently, the CDK1 inhibitor RO-3306 is less active in a TRAP1-high background. Finally, a significant correlation was observed between TRAP1 and Ki67, CDK1 and/or MAD2 expression in breast, colorectal, and lung human tumour specimens. This study represents the first evidence that TRAP1 is relevant in the control of the complex machinery that governs cell cycle progression and mitotic entry and provides a strong rationale to regard TRAP1 as a biomarker to select tumours with deregulated cell cycle progression and thus likely poorly responsive to novel cell cycle inhibitors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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TRAP1 a viable therapeutic target for future cancer treatments
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Matteo LandriscinaAbstract:ABSTRACTIntroduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.Expert opinion: TRAP1 targeting may represent a promising stra...
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TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma
Oncotarget, 2017Co-Authors: Francesca Maddalena, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Vittorio Simeon, Giulia Vita, Annamaria Bochicchio, Luciana Possidente, Valeria Li BergolisAbstract:// Francesca Maddalena 1 , Vittorio Simeon 1 , Giulia Vita 2 , Annamaria Bochicchio 3 , Luciana Possidente 2 , Lorenza Sisinni 1 , Giacomo Lettini 1 , Valentina Condelli 1 , Danilo Swann Matassa 4 , Valeria Li Bergolis 5 , Alberto Fersini 6 , Sante Romito 5 , Michele Aieta 3 , Antonio Ambrosi 6 , Franca Esposito 4 , Matteo Landriscina 1, 5 1 Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 2 Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 3 Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy 6 General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy Correspondence to: Matteo Landriscina, email: matteo.landriscina@unifg.it Franca Esposito, email: franca.esposito@unina.it Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival Received: November 02, 2016 Accepted: January 09, 2017 Published: February 03, 2017 ABSTRACT 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.
Franca Esposito - One of the best experts on this subject based on the ideXlab platform.
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TRAP1 regulates wnt β catenin pathway through lrp5 6 receptors expression modulation
International Journal of Molecular Sciences, 2020Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Michele Pietrafesa, Fabiana Crispo, Pietro Zoppoli, Ilaria Laurenzana, Alessandro Sgambato, Matteo LandriscinaAbstract:Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
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TRAP1 regulation of cancer metabolism dual role as oncogene or tumor suppressor
Genes, 2018Co-Authors: Danilo Swann Matassa, Matteo Landriscina, Ilenia Agliarulo, Rosario Avolio, Franca EspositoAbstract:Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure.
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TRAP1 a viable therapeutic target for future cancer treatments
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Matteo LandriscinaAbstract:ABSTRACTIntroduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.Expert opinion: TRAP1 targeting may represent a promising stra...
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TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial mesenchymal transition
Cell Death and Disease, 2016Co-Authors: Maria Rosaria Amoroso, Matteo Landriscina, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Ilenia Agliarulo, Rosario Avolio, Hani Gabra, Franca EspositoAbstract:Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC. At molecular level, downregulation of TRAP1 associates with higher expression of p70S6K, a kinase frequently active in OC with emerging roles in cell migration and tumor metastasis. Indeed, TRAP1 silencing in different OC cells induces upregulation of p70S6K expression and activity, enhancement of cell motility and epithelial–mesenchymal transition (EMT). Consistently, in a large cohort of OC patients, TRAP1 expression is reduced in tumor metastases and directly correlates with the epithelial marker E-Cadherin, whereas it inversely correlates with the transcription factor Slug and the matrix metallopeptidases 2 and 9. Strikingly, pharmacological inhibition of p70S6K reverts the high motility phenotype of TRAP1 knock-down cells. However, although p70S6K inhibition or silencing reduces the expression of the transcription factors Snail and Slug, thus inducing upregulation of E-Cadherin expression, it is unable to revert EMT induced by TRAP1 silencing; furthermore, p70S6K did not show any significant correlation with EMT genes in patients, nor with overall survival or tumor stage, suggesting an independent and predominant role for TRAP1 in OC progression. Altogether, these results may provide novel approaches in OC with reduced TRAP1 expression, which could be resistant to therapeutic strategies based on the inhibition of the p70S6K pathway, with potential future intervention in OC invasion and metastasis.
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targeting TRAP1 as a downstream effector of braf cytoprotective pathway a novel strategy for human braf driven colorectal carcinoma
Oncotarget, 2015Co-Authors: Valentina Condelli, Francesca Maddalena, Maria Rosaria Amoroso, Annamaria Piscazzi, Franca Esposito, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Giuseppe Palladino, Matteo LandriscinaAbstract:// Valentina Condelli 1, * , Francesca Maddalena 1, * , Lorenza Sisinni 1 , Giacomo Lettini 1 , Danilo Swann Matassa 2 , Annamaria Piscazzi 3 , Giuseppe Palladino 3 , Maria Rosaria Amoroso 2 , Franca Esposito 2 , Matteo Landriscina 3 1 Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy 2 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy 3 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy * These authors have contributed equally to this work Correspondence to: Matteo Landriscina, e-mail: matteo.landriscina@unifg.it Franca Esposito, e-mail: franca.esposito@unina.it Keywords: BRAF, TRAP1, apoptosis, colon cancer, drug resistance Received: April 13, 2015 Accepted: June 01, 2015 Published: June 13, 2015 ABSTRACT The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination, since BRAF down-regulation, ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition. Since TRAP1 is upregulated in human colorectal carcinomas (CRCs) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies, the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated. This study reports that BRAF cytoprotective signaling involves TRAP1-dependent inhibition of the mitochondrial apoptotic pathway. It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation, a condition associated with resistance to apoptosis. Consistently, a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug-resistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells. Thus, TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells.
Giacomo Lettini - One of the best experts on this subject based on the ideXlab platform.
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TRAP1 enhances warburg metabolism through modulation of pfk1 expression activity and favors resistance to egfr inhibitors in human colorectal carcinomas
Molecular Oncology, 2020Co-Authors: Francesca Maddalena, Valentina Condelli, Danilo Swann Matassa, Giacomo Lettini, Valeria Li Bergolis, Consiglia Pacelli, Rosella Scrima, Michele Pietrafesa, Fabiana Crispo, Annamaria PiscazziAbstract:Metabolic rewiring is a mechanism of adaptation to unfavorable environmental conditions and tumor progression. TRAP1 is an HSP90 molecular chaperone upregulated in human colorectal carcinomas (CRCs) and responsible for downregulation of oxidative phosphorylation (OXPHOS) and adaptation to metabolic stress. The mechanism by which TRAP1 regulates glycolytic metabolism and the relevance of this regulation in resistance to EGFR inhibitors were investigated in patient-derived CRC spheres, human CRC cells, samples, and patients. A linear correlation was observed between TRAP1 levels and 18 F-fluoro-2-deoxy-glucose (18 F-FDG) uptake upon PET scan or GLUT1 expression in human CRCs. Consistently, TRAP1 enhances GLUT1 expression, glucose uptake, and lactate production and downregulates OXPHOS in CRC patient-derived spheroids and cell lines. Mechanistically, TRAP1 maximizes lactate production to balance low OXPHOS through the regulation of the glycolytic enzyme phosphofructokinase-1 (PFK1); this depends on the interaction between TRAP1 and PFK1, which favors PFK1 glycolytic activity and prevents its ubiquitination/degradation. By contrast, TRAP1/PFK1 interaction is lost in conditions of enhanced OXPHOS, which results in loss of TRAP1 regulation of PFK1 activity and lactate production. Notably, TRAP1 regulation of glycolysis is involved in resistance of RAS-wild-type CRCs to EGFR monoclonals. Indeed, either TRAP1 upregulation or high glycolytic metabolism impairs cetuximab activity in vitro, whereas TRAP1 targeting and/or inhibition of glycolytic pathway enhances cell response to cetuximab. Finally, a linear correlation between 18 F-FDG PET uptake and poor response to cetuximab in first-line therapy in human metastatic CRCs was observed. These results suggest that TRAP1 is a key determinant of CRC metabolic rewiring and favors resistance to EGFR inhibitors through regulation of glycolytic metabolism.
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TRAP1 regulates wnt β catenin pathway through lrp5 6 receptors expression modulation
International Journal of Molecular Sciences, 2020Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Michele Pietrafesa, Fabiana Crispo, Pietro Zoppoli, Ilaria Laurenzana, Alessandro Sgambato, Matteo LandriscinaAbstract:Wnt/β-Catenin signaling is involved in embryonic development, regeneration, and cellular differentiation and is responsible for cancer stemness maintenance. The HSP90 molecular chaperone TRAP1 is upregulated in 60–70% of human colorectal carcinomas (CRCs) and favors stem cells maintenance, modulating the Wnt/β-Catenin pathway and preventing β-Catenin phosphorylation/degradation. The role of TRAP1 in the regulation of Wnt/β-Catenin signaling was further investigated in human CRC cell lines, patient-derived spheroids, and CRC specimens. TRAP1 relevance in the activation of Wnt/β-Catenin signaling was highlighted by a TCF/LEF Cignal Reporter Assay in Wnt-off HEK293T and CRC HCT116 cell lines. Of note, this regulation occurs through the modulation of Wnt ligand receptors LRP5 and LRP6 that are both downregulated in TRAP1-silenced cell lines. However, while LRP5 mRNA is significantly downregulated upon TRAP1 silencing, LRP6 mRNA is unchanged, suggesting independent mechanisms of regulation by TRAP1. Indeed, LRP5 is regulated upon promoter methylation in CRC cell lines and human CRCs, whereas LRP6 is controlled at post-translational level by protein ubiquitination/degradation. Consistently, human CRCs with high TRAP1 expression are characterized by the co-upregulation of active β-Catenin, LRP5 and LRP6. Altogether, these data suggest that Wnt/β-Catenin signaling is modulated at multiple levels by TRAP1.
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new TRAP1 and hsp90 chaperone inhibitors with cationic components preliminary studies on mitochondrial targeting
Bioorganic & Medicinal Chemistry Letters, 2018Co-Authors: Riccardo Rondanin, Lorenza Sisinni, Giacomo Lettini, Daniele Simoni, Paola Oliva, Riccardo Baruchello, Cristiana Costantini, Claudio Trapella, Tatiana Bernardi, Michele PietrafesaAbstract:Abstract TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.
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TRAP1 a viable therapeutic target for future cancer treatments
Expert Opinion on Therapeutic Targets, 2017Co-Authors: Giacomo Lettini, Francesca Maddalena, Franca Esposito, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Maria Paola Costi, Daniele Simoni, Matteo LandriscinaAbstract:ABSTRACTIntroduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.Expert opinion: TRAP1 targeting may represent a promising stra...
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TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma
Oncotarget, 2017Co-Authors: Francesca Maddalena, Valentina Condelli, Lorenza Sisinni, Danilo Swann Matassa, Giacomo Lettini, Vittorio Simeon, Giulia Vita, Annamaria Bochicchio, Luciana Possidente, Valeria Li BergolisAbstract:// Francesca Maddalena 1 , Vittorio Simeon 1 , Giulia Vita 2 , Annamaria Bochicchio 3 , Luciana Possidente 2 , Lorenza Sisinni 1 , Giacomo Lettini 1 , Valentina Condelli 1 , Danilo Swann Matassa 4 , Valeria Li Bergolis 5 , Alberto Fersini 6 , Sante Romito 5 , Michele Aieta 3 , Antonio Ambrosi 6 , Franca Esposito 4 , Matteo Landriscina 1, 5 1 Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 2 Pathology, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 3 Medical Oncology Units, IRCCS, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Medical Oncology, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy 6 General Surgery Units, Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy Correspondence to: Matteo Landriscina, email: matteo.landriscina@unifg.it Franca Esposito, email: franca.esposito@unina.it Keywords: TRAP1, client proteins, colorectal carcinoma, protein signature, overall survival Received: November 02, 2016 Accepted: January 09, 2017 Published: February 03, 2017 ABSTRACT 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.
