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Recent advances in the function of the 67 kDa laminin receptor and its targeting for personalized therapy in cancer
No full textThe 67 kDa high affinity laminin receptor (67LR) is a non integrin cell surface receptor for laminin, the major component of basement membranes. Interactions between 67LR and laminin play a major role in mediating cell adhesion, migration, proliferation and survival. 67LR derives from homo- or hetero-dimerization of a 37 kDa cytosolic precursor (37LRP), most probably by fatty acid acylation. Interestingly, 37LRP, also called p40 or OFA/iLR (oncofetal antigen/immature laminin receptor), is a multifunctional protein with a dual activity in the cytoplasm and in the nucleus. In the cytoplasm, 37LRP it is associated with the 40S subunit of ribosome, playing a critical role in protein translation and ribosome biogenesis while in the nucleus is tightly associated with nuclear structures, and bound to components of the cytoskeleton, such as tubulin and actin. 67LR is mainly localized in the cell membrane, concentrated in lipid rafts. Acting as a receptor for laminin is not the only function of 67LR; indeed, it also acts as a receptor for viruses, bacteria and prions. 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. The primary function of 67LR in cancer is to promote tumor cell adhesion to basement membranes, the first step in the invasion-metastasis cascade. Thus, 67LR is overexpressed in neoplastic cells as compared to their normal counterparts and its overexpression is considered a molecular marker of metastatic aggressiveness in cancer of many tissues, including breast, lung, ovary, prostate, stomach, thyroid and also in leukemia and lymphomas. Thus, inhibiting 67LR binding to laminin could be a feasible approach to block cancer progression. Here, we review the current understanding of the structure and function of this molecule, highlighting its role in cancer invasion and metastasis and reviewing the various therapeutic options targeting this receptor that could have a promising future application
Discovery of new small molecules inhibiting 67 kDa laminin receptor interaction with laminin and cancer cell invasion
No full textThe 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L. NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion. A subsequent hierarchical similarity search with NSC47924 led to the identification of additional four compounds inhibiting LR-293 cell binding to LM: NSC47923, NSC48478, NSC48861, and NSC48869, with IC50 values of 1.99, 1.76, 3.4, and 4.0 μmol/L, respectively, and able to block in vitro cancer cell invasion. These compounds are promising scaffolds for future drug design and discovery efforts in cancer progression
67 kDa Laminin Receptor (67LR) Involvement in the Trafficking of Normal and Leukemic Hematopoietic Stem Cells; Computer-Aided Identification of a Small Inhibitory Molecule
No full textThe 67 kDa laminin receptor (67LR) is a cell-surface receptor with high affinity for laminin (LM), which plays a key role in tumour progression. 67LR is also involved in normal human T lymphocytes homing and in acute myeloid leukaemia (AML), lymphoma and myeloma cell adhesion and migration.
Recently, we demonstrated 67LR involvement in granulocyte colony-stimulating factor (G-CSF)-induced mobilization of CD34+ hematopoietic stem cells (HSCs), in human healthy donors. 67LR has also been shown to contribute to HSC homing to BM after transplantation, in mice. We now investigated the role of 67LR in the trafficking of leukemic CD34+ HSCs and identified a 67LR inhibitory small molecule.
Flow cytometric analysis showed a strong upregulation of 67LR expression in BM as well as in peripheral blood (PB) CD34+ cells from acute myeloid leukemia (AML) patients, as compared to normal BM and PB CD34+ cells. Then, we investigated whether 67LR upregulation could modulate CD34+ leukemic cell adhesion and migration to LM and stromal derived factor 1 (SDF1), the key chemokine in HSC trafficking. 67LR-transfected CD34+ cells from the KG1 cell line showed increased migration toward LM and SDF1, as compared to untransfected cells; on the contrary, 67LR overexpression did not increase CD34+ KG1 cell adhesion to LM. 67LR activation by LM determined increased phosphorylation of p38 MAP Kinase, protein Kinase C and calcium/calmodulin-dependent protein kinase II.
Using the high resolution crystal structure of 67LR (PDB code: 3BCH), we identified 46 compounds that were predicted to interact with a previously identified LM-binding site on 67LR. Of these 46 chemical hits, compound 1-((4-methoxyphenylamino)methyl)naphthalen-2-ol, termed
NSC 47924, specifically inhibited 67LR-mediated cell adhesion, migration and proliferation to LM.
Leukemic cells undergo changes in adhesive properties that allow their migration into the circulation, leading to development of extramedullary disease. Our data show that 67LR overexpression is associated with a migratory phenotype both in cytokine-stimulated normal CD34+
HSCs and in leukemic CD34+ HSCs. Moreover, we demonstrated that 67LR function can be
specifically blocked by a newly-identified small molecule, making 67LR a promising therapeutical target
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
Inside the function of the 67 kDa laminin receptor (67LR): a new promising target for cancer drug discovery by structure-based virtual screening
No full textThe 67 kDa laminin receptor (67LR) is a non-integrin cell-surface receptor for the extracellular matrix derived from the dimerization of a 37 kDa cytosolic precursor (37LRP). 67LR is highly expressed in human cancers and widely recognized as a molecular marker of metastatic aggressiveness.
Phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) is an anti-apoptotic protein whose expression is increased in several human cancers. In addition to apoptosis, PED/PEA-15 is involved in the regulation of other major cellular functions, including cell adhesion, migration, proliferation and glucose metabolism.
A yeast two-hybrid screening identified 67LR as a PED/PEA-15 interacting partner. PED/PEA-15 molecular interaction with 67LR was confirmed by pull-down experiments on lysates of PED/PEA-15 transfected HEK-293 cells. Overexpressed and endogenous PED/PEA-15 co-immunoprecipitated with 67LR in PED/PEA-15 transfected HEK-293 cells and in U-373 glioblastoma cells, respectively.
PED/PEA-15 overexpression significantly increased 67LR-mediated HEK-293 cell adhesion and migration to laminin that, in turn, determined PED/PEA-15 phosphorylation both in Ser-104 and Ser-116, through CamKII and PKC activation, thus enabling cell proliferation and resistance to apoptosis.
Therefore, 67LR binding to laminin induces, through interaction with PED/PEA-15, signals that may be crucial for tumor cell survival in a poor microenvironment. Indeed, high 67LR expression predicts for a more aggressive disease in several types of cancer.
These considerations prompted us to search for small molecules that might target 67LR activities. Since cancer cells overexpress 67LR, these compounds are expected to be cancer cell specific and minimally toxic. We conducted a computational screening of a diversity library of small molecules using the recently solved 67LR crystal structure, focusing on residues showed to be important for laminin binding. This analysis identified a lead compound that was characterized for its effects. This lead compound, NSC47924, could be the basis for the development of a new class of anti-cancer drugs, specifically targeting tumor invasion and metastasis
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
Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials
No full textAtherosclerosis is a progressive inflammatory disease leading to mortality and morbidity in the civilized world. Atherosclerosis manifests as an accumulation of plaques in the intimal layer of the arterial wall that, by its subsequent erosion or rupture, triggers cardiovascular diseases. Diabetes mellitus is a well-known risk factor for atherosclerosis. Indeed, Type 2 diabetes mellitus patients have an increased risk of atherosclerosis and its associated-cardiovascular complications than non-diabetic patients. Sodium-glucose co-transport 2 inhibitors (SGLT2i), a novel anti-diabetic drugs, have a surprising advantage in cardiovascular effects, such as reducing cardiovascular death in a patient with or without diabetes. Numerous studies have shown that atherosclerosis is due to a significant inflammatory burden and that SGLT2i may play a role in inflammation. In fact, several experiment results have demonstrated that SGLT2i, with suppression of inflammatory mechanism, slows the progression of atherosclerosis. Therefore, SGLT2i may have a double benefit in terms of glycemic control and control of the atherosclerotic process at a myocardial and vascular level. This review elaborates on the anti-inflammatory effects of sodium-glucose co-transporter 2 inhibitors on atherosclerosis
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