Author Correction: LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Erratum for: LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. [Nature. 2016

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

Use of interrupter technique in assessment of bronchial responsiveness in normal subjects

BACKGROUND: A number of subjects, especially the very young and the elderly, are unable to cooperate and to perform forced expiratory manoeuvres in the evaluation of bronchial hyperresponsiveness (BHR). The objective of our study was to investigate the use of the interrupter technique as a method to measure the response to provocation and to compare it with the conventional PD(20 )FEV(1). METHODS: We studied 170 normal subjects, 100 male and 70 female (mean ± SD age, 38 ± 8.5 and 35 ± 7.5 years, respectively), non-smoking from healthy families. These subjects had no respiratory symptoms, rhinitis or atopic history. A dosimetric cumulative inhalation of methacholine was used and the response was measured by the dose which increases baseline end interruption resistance by 100% (PD(100)Rint, EI) as well as by percent dose response ratio (DRR). RESULTS: BHR at a cut-off level of 0.8 mg methacholine exhibited 31 (18%) of the subjects (specificity 81.2%), 21 male and 10 female, while 3% showed a response in the asthmatic range. The method was reproducible and showed good correlation with PD(20)FEV(1 )(r = 0.76, p < 0.005), with relatively narrow limits of agreement at -1.39 μmol and 1.27 μmol methacholine, respectively, but the interrupter methodology proved more sensitive than FEV(1 )in terms of reactivity (DRR). CONCLUSIONS: Interrupter methodology is clinically useful and may be used to evaluate bronchial responsiveness in normal subjects and in situations when forced expirations cannot be performed

Natural agents against neutrophil involvement in H.Pylori induced chronic gastritis

Helicobacter pylori infection is one of the widely spread human infections and the major risk for peptic ulcer disease, and gastric cancer and cause for chronic gastric inflammation. The major virulence factors in the development of gastric inflammation are VacA, CagA and HPNAP. HPNAP stimulates the production of reactive oxygen intermediates (ROIs) of human neutrophils and monocytes and promotes neutrophil adhesion to endothelial cells thereby causing mucosal damage. Agents (natural or chemical) inhibiting the HPNAP mediated neutrophil activation might be of great medical importance. According to current published data infiltration of neutrophils and mononuclear cells is significantly decreased due to CAPE mediated NF-kB suppression. In addition, according to our previous investigations AGPs, isolated from Pistacia lentiscus var Chia, inhibit neutrophil activation as well as neutrophil adhesion to endothelial cells. The emerging resistance of H.pylori to antibiotic treatment which provokes treatment failure and re-infection necessitates the investigation towards new forms of prevention and therapy of H.pylori induced chronic gastritis. © 2010 Nova Science Publishers, Inc. All rights reserved

Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47 phox

Akt activation up-regulates the intracellular levels of reactive oxygen species (ROS) by inhibiting ROS scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate ROS by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of ROS is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcrip-tional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidant N-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression in p53 −/− and INK4a −/− /Arf −/− mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation , despite the induction of high levels of ROS. The induction of ROS by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47 phox , which results in NADPH oxidase activation. Expression of Akt3 in p47 phox−/− MEFs failed to induce ROS and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47 phox , but not by the phosphorylation site mutant of p47 phox. In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important, Akt3 alterations correlate with a higher frequency of mutation of p53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response. Akt isoforms | NADPH oxidase | oxidative stress | DNA damage | cance