47 research outputs found
TRAP1 regulates stemness through Wnt/β-catenin pathway in human colorectal carcinoma
Colorectal carcinoma (CRC) is a common cause of cancer-related death worldwide. Indeed, treatment failures are triggered by cancer stem cells (CSCs) that give rise to tumor repopulation upon initial remission. Thus, the role of the heat shock protein TRAP1 in stemness was investigated in CRC cell lines and human specimens, based on its involvement in colorectal carcinogenesis, through regulation of apoptosis, protein homeostasis and bioenergetics. Strikingly, co-expression between TRAP1 and stem cell markers was observed in stem cells located at the bottom of intestinal crypts and in CSCs sorted from CRC cell lines. Noteworthy, TRAP1 knockdown reduced the expression of stem cell markers and impaired colony formation, being the CSC phenotype and the anchorage-independent growth conserved in TRAP1-rich cancer cells. Consistently, the gene expression profiling of HCT116 cells showed that TRAP1 silencing results in the loss of the stem-like signature with acquisition of a more-differentiated phenotype and the downregulation of genes encoding for activating ligands and target proteins of Wnt/β-catenin pathway. Mechanistically, TRAP1 maintenance of stemness is mediated by the regulation of Wnt/β-catenin signaling, through the modulation of the expression of frizzled receptor ligands and the control of β-catenin ubiquitination/phosphorylation. Remarkably, TRAP1 is associated with higher expression of β-catenin and several Wnt/β-catenin target genes in human CRCs, thus supporting the relevance of TRAP1 regulation of β-catenin in human pathology. This study is the first demonstration that TRAP1 regulates stemness and Wnt/β-catenin pathway in CRC and provides novel landmarks in cancer biology and therapeutics
TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition
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
Mitochondria are devoid of poly(ADP‐ribose)polymerase‐1, but harbor its product oligo(ADP‐ribose)
The heat shock protein TRAP1 is involved in translational control: a novel role in the quality control of mitochondrial proteins
TRAP1 role in endoplasmic reticulum stress protection favors resistance to anthracyclins in breast carcinoma cells
Preliminary characterization of pharmacodynamic biomarkers for LR-peptide growth inhibition of ovarian cancer (OC) cells models.
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Epidemiology of a phocine distemper virus outbreak along the North Atlantic coast of the United States
Due to an increase in pinniped strandings with consistent pathological findings throughout the North Atlantic coast of the United States during the summer and fall of 2006, an unusual mortal- ity event (UME) was declared by the National Oceanic and Atmospheric Administration's (NOAA) National Marine Fisheries Service (NMFS) on 20 October 2006. The goals of this investigation were to describe the magnitude and duration of the peak in mortalities involved in the UME and to evaluate associations with potential causative agents. Seal strandings during the UME were compared to historical strandings in the area to characterize the epidemiologic pat- terns of the UME. Temporal increases in phocine distemper virus (PDV) prevalence as detected by serology and polymerase chain reaction (PCR) were significantly correlated with increased seal stranding frequency. During July to October 2006, there was a significant spatial and tempo- ral cluster of PDV positive seals centered near Cape Ann, Massachusetts. Our findings provide evidence that PDV infections increased in harbor seals along the North Atlantic coast of the U.S. in 2006, and PDV likely played a role in a UME that involved harbor seals (Phoca vitulina), harp seals Phoca groenlandica), hooded seals (Cystophora cristata), and gray seals (Halichoerus grypus)