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Chairperson EUTROC- Mayo Conference-Berlin - Preliminary characterization of pharmacodynamic biomarkers for LR-peptide growth inhibition of ovarian cancer (OC) cell models.
No full textPreliminary characterization of pharmacodynamic biomarkers for LR-peptide growth inhibition of ovarian cancer (OC) cell models.
M.R.Amorosoa,b, G.Marvertib, F.Genovese, DS. Matassab, J.HEllemanc, E.Bernsc, F.Espositob*, MP Costib*.
aDept. Biomedical Sciences and cDept. Life Science, Via Campi 287-183, University of Modena and Reggio Emilia, 41125, Modena, Italy; Dept. of Medical Oncology, Erasmus University Medical Center - Cancer Center, PO Box 2040, 3000 CA, Rotterdam, Netherlands. bDepartment of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Pansini 5, Naples 80131, Italy.
LR-peptide is an inhibitor of human Thymidylate synthase (TS) through the stabilization of its inactive form as shown in drug-protein interaction experiments (1). Our previous findings demonstrated an inhibition of ovarian cancer cell growth at 2-4 μM in four cis-platin sensitive and resistant ovarian cancer cell-lines, i.e. A2780 and A2780/CP, 2008 and C13. The level of inhibition caused by LR-peptide is similar to that of paclitaxel, a first line drug in OC therapy. Mass spectrometry differential proteomic studies were performed on A2780 OC cell models in which untreated cells were examined in comparison with LR-peptide treated cells (2). Bioinformatic analysis of the results led to the identification of at least 10 proteins that were modulated upon LR-peptide treatment. Among them TRAP1 an antiapoptotic mitochondrial HSP75 protein was observed. This result was the starting point for a deeper understanding of the role of the combined TRAP1/DHFR/hTS modulation in ovarian cancer cells. We first studied the role of TRAP1 alone in OC cell models. We treated a panel of ovarian cancer cells (including IGROV1 and COV504) with paclitaxel, whose cytotoxic activity involves the activation of ER (endoplasmic reticulum) stress pathways. TRAP1 shows a protective role from ER stress, as reported previously (3). We observed that upon 1-hour exposure to a sub-lethal concentration of paclitaxel, cells expressing higher TRAP1 levels (IGROV1) showed a weak activation of ER stress sensors. such as phospho PERK, phospho eIf2alpha and Grp78/BiP. COV504 cell line express lower level of TRAP1, are more sensitive to paclitaxel treatment, showing an hyperactivation of ER stress markers. Higher concentrations of paclitaxel for longer times led to apoptotic processes as confirmed by stronger activation of the ER-stress induced caspase 12, in COV cells than in IGROV cell line. These data confirm the protective role of TRAP1 against paclitaxel induced ER stress, offering a possible mechanism of drug resistance in ovarian cancer.
1.Cardinale D. et al., PNAS 2011.
2. Proceedings EPS32 Athen 2013 p_466
3. Amoroso MR, et al.Cell Death Differ. 2012
Acknowledgement
This work has been supported by AIRC-DROC 10474 project to MPC
TRAP1 and the calcium binding protein sorcin interact in mitochondria and protect cells against apoptosis induced by antiblastic agents
No full textFunctional characterization of TRAP1 pathway in multidrug resistance in human colorectal carcinoma.
No full textHeat shock proteins, cell survival and drug resistance: the mitochondrial chaperone TRAP1, a potential novel target for ovarian cancer therapy
No full textProtein homeostasis is a highly complex network of molecular interactions governing the
health and life span of the organism. Molecular chaperones, mainly heat shock proteins (HSP) and other stressinducible
proteins abundantly expressed in multiple compartments of the cell, are major modulators of protein
homeostasis. TRAP1 is a mitochondrial HSP involved in protection against oxidant-induced DNA damage and
apoptosis. It was recently described as a component of a mitochondrial pathway selectively up-regulated in
tumor cells which antagonizes the proapoptotic activity of cyclophilin D, a mitochondrial permeability
transition pore regulator, and is responsible for the maintenance of mitochondrial integrity, thus favoring cell
survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective
tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer
therapy. Preliminary data suggest that TRAP1 may be a valuable biomarker in ovarian cancers: in fact, TRAP1
levels are signi!cantly higher in cisplatin-resistant ovarian tumors and ovarian carcinoma cell lines.
Conclusions. While major advances have been made in understanding the genetics and molecular biology of
cancer, given the considerable heterogeneity of ovarian cancer, the introduction of novel targeted therapies and
the consequent selection of treatments based on the molecular pro!le of each tumor may have a major impact
on the management of this malignancy and might contribute to building a new era of personalized medicine
The ribonuclease/angiogenin inhibitor is also present in mitochondria and nuclei.
No full textThe data presented here show for the first time that the protein known as "ribonuclease (RNase) inhibitor" (RI or RNH1) is present not only in the cell cytosol, but also in mitochondria, the central organelles in cell redox homeostasis. This finding directly correlates with the reported ability of RI to protect the cell from oxidative stress, with its sensitivity to oxidation and reactivity as a reactive oxygen species scavenger. While this study was carried out we also surprisingly discovered the presence of RI in the cell nucleus. We deem that these data open new views in the investigation on the cellular role(s) of the RI
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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