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

LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities

Detection of somatostatin receptors in human osteosarcoma

Background: The location of osteosarcoma in the metaphysis as well as the age of the patients during the most rapid tumour growth suggest that factors related to skeletal growth are involved in the pathogenesis of this tumour. In this aspect this study aims to detect somatostatin receptors in human osteosarcomas and correlate this finding with the clinical outcome of the tumour. Patients and methods: Immunohistochemical staining for the presence of somatostatin receptors as well as overall survival and disease free survival rates were retrospectively studied in twenty-nine osteosarcoma patients. Results: Four osteosarcomas with several aggressive biologic behaviour expressed somatostatin receptors. In these four young patients the event free rate was 0% and the overall survival rate was 50% at 4, 3 years. In contrast the event free survival rate of the twenty-five patients with negative somatostatin receptor status was 72% with an overall survival rate of 76% at 4,3 years. Conclusion: The present study demonstrates the existence of somatostatin receptors in human osteosarcoma. Tumours expressing somatostatin receptors seemed to be aggressive with a very low disease free and overall survival rate compared to osteosarcoma with negative receptor status. © 2008 Ioannou et al; licensee BioMed Central Ltd

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