Anti-neoplastic effect of epigallocatechin gallate on breast cancer cells through glucose metabolism

Breast cancer (BC) is the primary cause of women cancer death, which could be prevented by EGCG that has been recently shown several health properties included anti-cancer, however the mechanism underpinning still poorly understood. In this study, several biological activities of both MCF7 and MDA-MB-231 cells were evaluated in response to EGCG. Cell viability and the role of Akt and AMPK inhibitor molecules, and sodium pyruvate on this viability, apoptosis, metastasis, and interestingly regulation of glucose metabolism were assessed. EGCG promoted cytotoxicity in both BC cell lines after 24h but not less. Co-incubated cells with Akt and AMPK inhibitors alongside EGCG significantly caused more reduction in cell viability compared to the effect of EGCG alone with maximum effect referred to Akt inhibitor. While supplemented sodium pyruvate significantly restored the decreases in cell viability. Remarkably, EGCG induced apoptosis through increased caspase 3/7 activation associated with upregulated Bax gene, in addition to anti-metastatic effect through decreasing cellular migration. Importantly, lactate production was sharply reduced after 6h (no alteration of viable cells) and 24h (decreased viable cells) concomitant with significant blocked glucose uptake in response to EGCG. In conclusion, EGCG could be a potential anti-migration, the anti-cancerous therapeutic agent through targeting cancer cells glucose metabolism

Exploiting tumour addiction with a serine and glycine-free diet.

Understanding cancer metabolism is key to unveil the Achilles’ heel of cancer cells and provide novel therapeutic interventions for patients. While the rerouting of metabolic pathways during development1 or cancer transformation and progression2, 3, 4 has been extensively characterised, the exact dynamic of these events, their distribution and frequency in the different tumour types, and the correlation with genetic background remain largely unknown. In a recent article published in Nature, Karen Vousden’s team assesses the effect of serine and glycine dietary restriction in autochthonous mouse tumour models driven by different oncogenes (Maddocks et al, 2017)5, leading to potential area of therapeutic intervention

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

Progress in creating a joint research agenda that allows networked long-term socio-ecological research in southern South America : addressing crucial technological and human capacity gaps limiting its application in Chile and Argentina

Since 1980, more than 40 countries have implemented long-term ecological research (LTER) programs, which have shown their power to affect advances in basic science to understand the natural world at meaningful temporal and spatial scales and also help link research with socially relevant outcomes. Recently, a disciplinary paradigmatic shift has integrated the human dimensions of ecosystems, leading to a long-term socio-ecological research (LTSER) framework to address the world's current environmental challenges. A global gap in LTER/LTSER only exists in the latitudinal range of 40–60°S, corresponding to Argentina and Chile's temperate/sub-Antarctic biome. A team of Chilean, Argentine and US researchers has participated in an ongoing dialogue to define not only conceptual, but also practical barriers limiting LTER/LTSER in southern South America. We have found a number of existing long-term research sites and platforms throughout the region, but at the same time it has been concluded an agenda is needed to create and implement further training courses for students, postdoctoral fellows and young scientists, particularly in the areas of data and information management systems. Since LTER/LTSER efforts in Chile and Argentina are incipient, instituting such courses now will enhance human and technical capacity of the natural science and resource community to improve the collection, storage, analysis and dissemination of information in emerging LTER/LTSER platforms. In turn, having this capacity, as well as the ongoing formalization of LTER/LTSER programs at national levels, will allow the enhancement of crucial collaborations and comparisons between long-term research programs within the region and between hemispheres and continents. For Spanish version of the entire article, see Online Supporting Information (Appendix S1).Desde 1980, más de cuarenta países han implementado programas de Investigación Ecológica a Largo Plazo (LTER por sus siglas en inglés), los cuales han mostrado su capacidad para influir sobre los avances en las ciencias básicas que permiten entender el mundo natural en escalas temporales y espaciales significativas, y también ayudar a enfocar la investigación hacia estudios socialmente relevantes. Recientemente, gracias a un cambio de paradigma en la disciplina, se integró también la dimensión humana de los ecosistemas, llevándola a un marco conceptual de Investigación Socio-Ecológica a Largo Plazo (LTSER por sus siglas en inglés) para enfrentar los desafíos medio-ambientales del mundo actual. Existe un vacío global en LTER/LTSER en el rango latitudinal de 40–60°S, correspondiente a los biomas templados/subantárticos de Argentina y Chile. Un equipo de investigadores chilenos, argentinos y estadounidenses ha trabajado por varios años para definir cuáles son la barreras que actualmente limitan la creación de una Red de LTER/LTSER en el sur de Sudamérica, no solamente en términos conceptuales, sino también a nivel práctico. Existe un buen número de sitios de investigación a largo plazo en la región, pero también concluimos que es necesario crear e implementar más cursos de capacitación para estudiantes, investigadores post-doctorales y jóvenes científicos, particularmente en las áreas de sistemas de manejo de datos e información. Considerando que los esfuerzos LTER/LTSER en Chile y Argentina son incipientes, este tipo de cursos podría mejorar la capacidad humana y técnica en la comunidad de las ciencias y los recursos naturales, así como mejorar los procesos de recolección, almacenamiento, análisis y difusión de la información. A su vez, la formalización de cursos de programas LTER/LTSER a nivel nacional para adquirir dicha capacidad de manejo de la información, permitirá un fortalecimiento crucial de las colaboraciones y comparaciones entre programas de investigación a largo plazo dentro de la región, y entre hemisferios y continentes. La versión en castellano del artículo se encuentra disponible en forma digital como Online Supporting Information S1.Fil: Anderson, Chistopher B. University of North Texas. Department of Biological Sciences; Estados UnidosFil: Celis-Diez, Juan Luis. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Bond, Barbara J.H.G. Oregon State University. Andrews Forest Long-Term Ecological Research Site. Department of Forest Ecosystems and Society; Estados UnidosFil: Martínez Pastur, Guillermo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Cientificas; ArgentinaFil: Little, Christian. Universidad Austral de Chile. Facultad de Ciencias. Instituto de Ciencias de la Tierra y Evolución; Chile. Fundación Centro de los Bosques Nativos FORECOS; ChileFil: Armesto, Juan J. Pontificia Universidad Católica de Valparaíso, Escuela de Agronomía; ChileFil: Ghersa, Claudio Marco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Austin, Amy Theresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; ArgentinaFil: Schlichter, Tomas Miguel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Grupo de Ecología Forestal; ArgentinaFil: Lara, Antonio. Fundación Centro de los Bosques Nativos FORECOS; Chile. Universidad Austral de Chile. Facultad de Ciencias Forestales y Recursos Naturales. Instituto de Silvicultura; ChileFil: Carmona, Martin. Universidad de Chile. Instituto de Ecologıa y Biodiversidad; ChileFil: Chaneton, Enrique Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura; Argentina. Universidad de Buenos Aires. Facultad de Agronomia. Departamento de Recursos Naturales y Ambiente; ArgentinaFil: Gutierrez, Julio R. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad. Centro de Estudios Avanzados en Zonas Aridas; ChileFil: Rozzi, Ricardo. Universidad de La Serena. Departamento de Biología. Instituto de Ecología y Biodiversidad; ChileFil: Vanderbilt, Kristin University of New Mexico. Department of Biology. Sevilleta Long-Term Ecological Research Site; Estados UnidosFil: Oyarce, Guillermo University of North Texas. Library and Information Sciences; Estados UnidosFil: Fernandez, Roberto J. University of North Texas, Department of Biological Sciences; Estados Unido

MiR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma

10.1371/journal.pone.0086872PLoS ONE91-POLN

Local Loss and Spatial Homogenization of Plant Diversity Reduce Ecosystem Multifunctionality

Biodiversity is declining in many local communities while also becoming increasingly homogenized across space. Experiments show that local plant species loss reduces ecosystem functioning and services, but the role of spatial homogenization of community composition and the potential interaction between diversity at different scales in maintaining ecosystem functioning remains unclear, especially when many functions are considered (ecosystem multifunctionality). We present an analysis of eight ecosystem functions measured in 65 grasslands worldwide. We find that more diverse grasslands—those with both species-rich local communities (α-diversity) and large compositional differences among localities (β-diversity)—had higher levels of multifunctionality. Moreover, α- and β-diversity synergistically affected multifunctionality, with higher levels of diversity at one scale amplifying the contribution to ecological functions at the other scale. The identity of species influencing ecosystem functioning differed among functions and across local communities, explaining why more diverse grasslands maintained greater functionality when more functions and localities were considered. These results were robust to variation in environmental drivers. Our findings reveal that plant diversity, at both local and landscape scales, contributes to the maintenance of multiple ecosystem services provided by grasslands. Preserving ecosystem functioning therefore requires conservation of biodiversity both within and among ecological communities

Indirect interaction between two native thistles mediated by an invasive exotic floral herbivore

Spatial and temporal variation in insect floral herbivory is common and often important. Yet, the determinants of such variation remain incompletely understood. Using 12 years of flowering data and 4 years of biweekly insect counts, we evaluated four hypotheses to explain variation in damage by the Eurasian flower head weevil, Rhinocyllus conicus, to the native North American wavyleaf thistle, Cirsium undulatum. The four factors hypothesized to influence weevil impact were variations in climate, weevil abundance, phenological synchrony, and number of flower heads available, either on wavyleaf thistle or on the other co-occurring, acquired native host plant (Platte thistle, Cirsium canescens), or on both. Climate did not contribute significantly to an explanation of variation in R. conicus damage to wavyleaf thistle. However, climate did influence weevil synchrony with wavyleaf flower head initiation, and phenological synchrony was important in determining R. conicus oviposition levels on wavyleaf thistle. The earlier R. conicus was active, the less it oviposited on wavyleaf thistle, even when weevils were abundant. Neither weevil abundance nor availability of wavyleaf flower heads predicted R. conicus egg load. Instead, the strongest predictor of R. conicus egg load on wavyleaf thistle was the availability of flower heads on Platte thistle, the more common, earlier flowering native thistle in the sand prairie. Egg load on wavyleaf thistle decreased as the number of Platte thistle flower heads at a site increased. Thus, wavyleaf thistle experienced associational defense in the presence of flowering by its now declining native congener, Platte thistle. These results demonstrate that prediction of damage to a native plant by an exotic insect may require knowledge of both likely phenological synchrony and total resource availability to the herbivore, including resources provided by other nontarget native species

PARP14 promotes the warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism

Allosteric pyruvate kinase-based "logic gate" synergistically senses energy and sugar levels in <i>Mycobacterium tuberculosis</i>

Pyruvate kinase (PYK) is an essential glycolytic enzyme that controls glycolytic flux and is critical for ATP production in all organisms, with tight regulation by multiple metabolites. Yet the allosteric mechanisms governing PYK activity in bacterial pathogens are poorly understood. Here we report biochemical, structural and metabolomic evidence that Mycobacterium tuberculosis (Mtb) PYK uses AMP and glucose-6-phosphate (G6P) as synergistic allosteric activators that function as a molecular "OR logic gate" to tightly regulate energy and glucose metabolism. G6P was found to bind to a previously unknown site adjacent to the canonical site for AMP. Kinetic data and structural network analysis further show that AMP and G6P work synergistically as allosteric activators. Importantly, metabolome profiling in the Mtb surrogate, Mycobacterium bovis BCG, reveals significant changes in AMP and G6P levels during nutrient deprivation, which provides insights into how a PYK OR gate would function during the stress of Mtb infection