Glycosylation of glycolipids in cancer: basis for development of novel therapeutic approaches

Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described.Fil: Daniotti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Vilcaes, Aldo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Torres Demichelis, Vanina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Ruggiero, Fernando Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Rodríguez Walker, Macarena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentin

Ganglioside synthesis by plasma membrane-associated sialyltransferase in macrophages

Gangliosides are constituents of the mammalian cell membranes and participate in the inflammatory response. However, little is known about the presence and enzymatic activity of ganglioside sialyltransferases at the cell surface of macrophages, one of the most important immune cells involved in the innate inflammatory process. In the present study, using biochemical and fluorescent microscopy approaches, we found that endogenous ST8Sia-I is present at the plasma membrane (ecto-ST8Sia-I) of murine macrophage RAW264.7 cells. Moreover, ecto-ST8Sia-I can synthetize GD3 ganglioside at the cell surface in lipopolysaccharide (LPS)-stimulated macrophages even when LPS-stimulated macrophages reduced the total ST8Sia-I expression levels. Besides, cotreatment of LPS with an inhibitor of nitric oxide (NO) synthase recovered the ecto-ST8Sia-I expression, suggesting that NO production is involved in the reduction of ST8Sia-I expression. The diminution of ST8Sia-I expression in LPS-stimulated macrophages correlated with a reduction of GD3 and GM1 gangliosides and with an increment of GD1a. Taken together, the data supports the presence and activity of sialyltransferases at the plasma membrane of RAW264.7 cells. The variations of ecto-ST8Sia-I and ganglioside levels in stimulated macrophages constitutes a promissory pathway to further explore the physiological role of this and others ganglioside metabolism-related enzymes at the cell surface during the immune response.Fil: Vilcaes, Aldo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; ArgentinaFil: Garbarino Pico, Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; ArgentinaFil: Torres Demichelis, Vanina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; ArgentinaFil: Daniotti, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentin

María la del Barrio protagoniza La Tempestad

La conquista de las indias orientales es una clave de lectura posible para una corriente de intelectuales latinoamericanos que dieron a La Tempestad de Shakespeare una centralidad en los debates en torno al colonialismo. La pieza es recorrida por figuras enunciativas que nos traen al presente el pasado español en América, el proceso de dominación en sus dimensiones imperialistas y patriarcales. Atravesar el vasto repertorio de interpretaciones sobre los destinos del continente americano que se despliegan en las páginas del pensamiento mestizo de la raza cósmica, convierte a esta tragedia que atraviesa territorios y tiempos en una tragedia transcolonial, una herida siempre abierta en la noche de nuestros días. Retomando a Gramsci que consideró específicamente a Shakespeare central para el melodrama trágico de la literatura popular italiana, María la del barrio protagoniza La Tempestad construye una relación entre la comunicación, la cultura popular y el colonialismo. Si la novela televisiva latinoamericana, y específicamente mexicana, expresa una cultura popular situada y heredera de sus tradiciones, las posiciones coloniales se escenifican bajo las apariencias de los ropajes de Thalia.Facultad de Periodismo y Comunicación Social (FPyCS

María la del Barrio protagoniza La Tempestad

La conquista de las indias orientales es una clave de lectura posible para una corriente de intelectuales latinoamericanos que dieron a La Tempestad de Shakespeare una centralidad en los debates en torno al colonialismo. La pieza es recorrida por figuras enunciativas que nos traen al presente el pasado español en América, el proceso de dominación en sus dimensiones imperialistas y patriarcales. Atravesar el vasto repertorio de interpretaciones sobre los destinos del continente americano que se despliegan en las páginas del pensamiento mestizo de la raza cósmica, convierte a esta tragedia que atraviesa territorios y tiempos en una tragedia transcolonial, una herida siempre abierta en la noche de nuestros días. Retomando a Gramsci que consideró específicamente a Shakespeare central para el melodrama trágico de la literatura popular italiana, María la del barrio protagoniza La Tempestad construye una relación entre la comunicación, la cultura popular y el colonialismo. Si la novela televisiva latinoamericana, y específicamente mexicana, expresa una cultura popular situada y heredera de sus tradiciones, las posiciones coloniales se escenifican bajo las apariencias de los ropajes de Thalia.Facultad de Periodismo y Comunicación Social (FPyCS

María la del Barrio protagoniza La Tempestad

La conquista de las indias orientales es una clave de lectura posible para una corriente de intelectuales latinoamericanos que dieron a La Tempestad de Shakespeare una centralidad en los debates en torno al colonialismo. La pieza es recorrida por figuras enunciativas que nos traen al presente el pasado español en América, el proceso de dominación en sus dimensiones imperialistas y patriarcales. Atravesar el vasto repertorio de interpretaciones sobre los destinos del continente americano que se despliegan en las páginas del pensamiento mestizo de la raza cósmica, convierte a esta tragedia que atraviesa territorios y tiempos en una tragedia transcolonial, una herida siempre abierta en la noche de nuestros días. Retomando a Gramsci que consideró específicamente a Shakespeare central para el melodrama trágico de la literatura popular italiana, María la del barrio protagoniza La Tempestad construye una relación entre la comunicación, la cultura popular y el colonialismo. Si la novela televisiva latinoamericana, y específicamente mexicana, expresa una cultura popular situada y heredera de sus tradiciones, las posiciones coloniales se escenifican bajo las apariencias de los ropajes de Thalia.Facultad de Periodismo y Comunicación Social (FPyCS

Dysregulated Expression of Glycolipids in Tumor Cells: From Negative Modulator of Anti-tumor Immunity to Promising Targets for Developing Therapeutic Agents

Glycolipids are complex molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found the gangliosides, which are sialylated glycolipids ubiquitously distributed on the outer layer of vertebrate plasma membranes. Changes in the expression of certain species of gangliosides have been described to occur during cell proliferation, differentiation and ontogenesis. However, the aberrant and elevated expression of gangliosides has been also observed in different types of cancer cells, thereby promoting tumor survival. Moreover, gangliosides are actively released from the membrane of tumor cells, having a strong impact on impairing anti-tumor immunity. Beyond the undesirable effects of gangliosides in cancer cells, a substantial number of cancer immunotherapies have been developed in recent years that have used gangliosides as the main target. This has resulted in successful immune cell- or antibody-responses against glycolipids, with promising results having been obtained in clinical trials. In this review, we provide a general overview on the metabolism of glycolipids, both in normal and tumor cells, as well as examining glycolipid-mediated immune modulation and the main successes achieved in immunotherapies using gangliosides as molecular targets

Ab Initio investigation of the interaction of H2 with lithium exchanged low-silica chabazites

The interaction of molecular hydrogen with the polarizing centers of lithiumexchanged chabazites with low Si/Al ratio (CHA-5/1 and CHA-3/1) was theoretically studied within a periodic approach at the B3LYP level of theory. The cation site preferences in both zeolites were determined and the H2 interaction was then studied by adding a molecule in the proximity of the different polarizing centers. The energetic features of the H2-Li2CHA-5/1 complex were also refined by using a cluster model cut out from the periodic structure in which the contribution of the dispersive forces to the interaction (absent at the B3LYP level of theory) were estimated at the MP2 level by means of an ONIOM2-like approach. Overall results show that the position of the polarizing center in the structure and its stability in the site is crucial for determining the sorption capacity of the zeolite. Lithium exchanged low-silica zeolites are shown to be only effective for hydrogen storage when the Al loading is at least 3:1. However, the highest predicted enthalpy of adsorption is around 10 kJ/mol and this indicates that they are far from fulfilling the conditions for practical application

Targeted delivery of immunotoxin by R24 antibody inhibit the clonogenic growth of CHO-K1^GD3+ cells. A

<p>) A schematical representation of the experimental procedure used in (<b>B</b> and <b>C</b>). <b>B</b>) CHO-K1^GD3+ cells (50–80 cells) were grown in 24-well plates previously coated with 0.5% agar in DMEM supplemented with 20% FBS. Cells were maintained at 37°C in a hummed atmosphere until cell colonies appeared (7 days, upper row. Colonies indicated with arrows). Then, cells were treated for 3 days (7+3 days, lower row) with 0.95 nM Saporin-Ab (Saporin-Ab, middle panel) or 30 nM R24/0.95 nM Saporin-Ab (R24/Saporin-Ab, right panel). CHO-K1^GD3+ cells maintained only with medium were used as negative control (control, left panel). The micrographs are representative of three independent experiments. <b>C</b>) Quantification of the colony area at 7 and 7+3 days at the different conditions indicated in <b>B</b>. Results were analyzed by ANOVA followed by Tukey’s multiple comparison test. Results are given as means±S.E. Note that the clonogenic growth of CHO-K1^GD3+ cells was severely affected only in presence of R24/Saporin-Ab (*** p<0.0001, respect to control condition at 7+3 days).</p

Immunotoxin inhibits CHO-K1^GD3+ and SK-Mel-28 cells colony formation. A

<p>) A schematical representation of the experimental procedure used in <b>B</b> and <b>C</b>. CHO-K1^GD3+(<b>B</b>) and SK-Mel-28 (<b>C</b>) cells (50–80 cells) were seed in 24-well plates previously coated with 0.5% agar in DMEM supplemented with 20% FBS. Cultures were supplemented with 0.95 nM Saporin-Ab or 30 nM R24/0.95 nM Saporin-Ab and maintained at 37°C in a hummed atmosphere. Quantification of the colony area was performed every day, but only indicated at 7 and 10 days. Cells maintained only with medium were used as negative control (control). Results were analyzed by ANOVA followed by Tukey’s multiple comparison test. Results are given as means±S.E. Note the drastic inhibition of colony formation only in presence of R24/Saporin-Ab.</p