Breaking up is hard to do: RalA, mitochondrial fission and cancer

The small GTPases RalA and RalB are activated downstream of oncogenic Ras. While activation of RalA is critically important for tumor initiation and growth of Ras-driven cancers, the highly similar small GTPase RalB is implicated in cell survival and metastasis. This difference in function between these two related proteins maps to the C-terminus, a 30 amino acid region that regulates subcellular localization and contains several potential phosphorylation sites. Here we discuss our recent evidence that phosphorylation by the mitotic kinase Aurora A promotes RalA relocalization to mitochondrial membranes, where it recruits the effector RalBP1 and the large dynamin-related GTPase Drp1 to promote mitochondrial fission. As upregulation of both RalA and Aurora A have been observed in human tumors, and phosphorylation of RalA at the site targeted by Aurora A promotes tumorigenesis, it is possible that regulation of mitochondrial fission is one mechanism by which RalA promotes cancer

Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

Background: Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods: To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results: The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion: In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways

Estimación de riesgo de cáncer gástrico en pacientes con gastritis crónica asociada a la infección por Helicobacter pylori en un escenario clínico

Antecedentes/Objetivo: La severidad de la gastritis crónica asociada con la infección por Helicobacter pylori (GCAHpI) juega un papel importante en la evaluación del riesgo potencial de desarrollar cáncer gástrico. Nuestro objetivo fue estimar el riesgo de cáncer gástrico de acuerdo con criterios histopatológicos y mediante la aplicación del índice de riesgo de cáncer gástrico (GCRI). Métodos: Se realizó análisis histopatológico de biopsias gástricas (cuerpo y antro) de pacientes adultos consecutivos que fueron sometidos a panendoscopia y el GCRI se aplicó en pacientes que presentaban evidencia de GCAHpI. Resultados: Se incluyeron 111 pacientes (77% mujeres) con una edad media de 38.6 ± 13.1. La infección activa por Helicobacter pylori (AHPI) se diagnosticó en 77 casos (69.40%). Del 45% de los casos con AHPI, 23% tuvieron pangastritis y 22% gastritis predominante en el cuerpo gástrico. Nueve casos fueron diagnosticados con metaplasia intestinal (8%), 7 de los cuales (77.70%) fueron del grupo AHPI. Veintiún por ciento de los pacientes con AHPI tenía un GCRI de 2 (18.10%) o 3 (2.50%) puntos (índice de riesgo alto), mientras que el 79.10% restante tuvieron un GCRI de 0 o 1 puntos (riesgo bajo índice). De los pacientes sin AHPI, ninguno de ellos tenía 3 puntos (p = 0.001). De los 18 pacientes que acumularon 2 o 3 puntos, 6 (33.30%) presentaron metaplasia intestinal (todos con pangastritis y gastritis en cuerpo), de los cuales 4 casos (66.60%) tenían AHPI. Conclusiones: El riesgo estimado de cáncer gástrico en pacientes con GCAHpI en el entorno clínico estudiado fue relativamente bajo y 5% de los pacientes tenían un fenotipo histopatológico asociado con un riesgo elevado de desarrollar cáncer gástrico

Solute diffusion is hindered in the mitochondrial matrix

Intracellular chemical reactions generally constitute reaction-diffusion systems located inside nanostructured compartments like the cytosol, nucleus, endoplasmic reticulum, Golgi, and mitochondrion. Understanding the properties of such systems requires quantitative information about solute diffusion. Here we present a novel approach that allows determination of the solvent-dependent solute diffusion constant (Dsolvent) inside cell compartments with an experimentally quantifiable nanostructure. In essence, our method consists of the matching of synthetic fluorescence recovery after photobleaching (FRAP) curves, generated by a mathematical model with a realistic nanostructure, and experimental FRAP data. As a proof of principle, we assessed Dsolvent of a monomeric fluorescent protein (AcGFP1) and its tandem fusion (AcGFP12) in the mitochondrial matrix of HEK293 cells. Our results demonstrate that diffusion of both proteins is substantially slowed by barriers in the mitochondrial matrix (cristae), suggesting that cells can control the dynamics of biochemical reactions in this compartment by modifying its nanostructure