Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.
ABSTRACT Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.
SourceAvailable from: Badrul Yahaya[Show abstract] [Hide abstract]
ABSTRACT: Despite significant advances in staging and therapies, lung cancer remains a major cause of cancer-related lethality due to its high incidence and recurrence. Clearly, a novel approach is required to develop new therapies to treat this devastating disease. Recent evidence indicates that tumours contain a small population of cells known as cancer stem cells (CSCs) that are responsible for tumour maintenance, spreading and resistant to chemotherapy. The genetic composition of CSCs so far is not fully understood, but manipulation of the specific genes that maintain their integrity would be beneficial for developing strategies to combat cancer. Therefore, the goal of this study isto identify the transcriptomic composition and biological functions of CSCs from non-small cell lung cancer (NSCLC). We isolated putative lung CSCs from lung adenocarcinoma cells (A549 and H2170) and normal stem cells from normal bronchial epithelial cells (PHBEC) on the basis of positive expression of stem cell surface markers (CD166, CD44, and EpCAM) using fluorescence-activated cell sorting. The isolated cells were then characterised for their self-renewal characteristics, differentiation capabilities, expression of stem cell transcription factor and in vivo tumouregenicity. The transcriptomic profiles of putative lung CSCs then were obtained using microarray analysis. Significantly regulated genes (p < 0.05, fold change (FC) > 2.0) in putative CSCs were identified and further analysed for their biological functions using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The putative lung CSCs phenotypes of CD166(+)/CD44(+) and CD166(+)/EpCAM(+) showed multipotent characteristics of stem cells, including the ability to differentiate into adipogenic and osteogenic cells, self-renewal, and expression of stem cell transcription factors such as Sox2 and Oct3/4. Moreover, the cells also shows the in vivo tumouregenicity characteristic when transplanted into nude mice. Microarray and bioinformatics data analyses revealed that the putative lung CSCs have molecular signatures of both normal and cancer stem cells and that the most prominent biological functions are associated with angiogenesis, migration, pro-apoptosis and anti-apoptosis, osteoblast differentiation, mesenchymal cell differentiation, and mesenchyme development. Additionally, self-renewal pathways such as the Wnt and hedgehog signalling pathways, cancer pathways, and extracellular matrix (ECM)-receptor interaction pathways are significantly associated with the putative lung CSCs. This study revealed that isolated lung CSCs exhibit the characteristics of multipotent stem cells and that their genetic composition might be valuable for future gene and stem cells therapy for lung cancer.BMC Cancer 02/2015; 15(84). DOI:10.1186/s12885-015-1086-3 · 3.32 Impact Factor
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ABSTRACT: RationaleGlycine is the smallest amino acid used in protein synthesis, but it is also a very important precursor for the biosynthesis of other nitrogen-containing metabolites, such as purine nucleosides and nucleotides for synthesis of RNA, DNA etc. Abnormalities in glycine metabolism therefore cause diseases such as cancer. A quick and unambiguous method to trace the metabolites arising from glycine is required for targeting defect points within metabolic networks.Methods This paper describes a method for using 15N-glycine to culture A549 cancer cells for use with high-resolution mass spectrometry (HRMS) and tandem mass spectrometry (HRMS2) that can detect the (M+1)/M pair peaks appearing in the cell metabolites. The 1 Da difference in the pair peaks can be used to point out and identify the nitrogen metabolites of glycine.ResultsThirteen nitrogen-containing metabolites derived from glycine were confirmed. Among them were metabolites containing purine, such as adenine, adenosine, AMP, ADP, ATP, S-adenosylmethionine and γ-glutathione; these were the most sensitive to the 15N-glycine-enrichment technique. Therefore, they are promising biomarkers for monitoring the glycine metabolism network.Conclusions The method developed here could be applied to investigations of metabolism of other amino acids, and for drug discovery studies targeting the enzymes related to amino acid metabolism. Copyright © 2015 John Wiley & Sons, Ltd.Rapid Communications in Mass Spectrometry 04/2015; 29(7). DOI:10.1002/rcm.7132 · 2.64 Impact Factor
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ABSTRACT: The progression of colorectal cancer is commonly characterized by accumulation of genetic or epigenetic abnormalities, altering regulation of gene expression as well as normal protein structures and functions. Nonetheless, there are some questions that remain to be elucidated, such as the origin of cancer cells and populations of cells initiating and propagating tumor development. Currently, there are two rival theories describing the process of carcinogenesis. One is the stochastic model, arguing that any cell is capable of initiating and triggering the development of cancer. Meanwhile, the cancer stem cell model hypothesizes that only a small fraction of stem cells possesses cancer-promoting properties. Typically, colorectal cancer stem cells (CSCs) share the same molecular signaling profiles with normal stem cells or embryonic stem cells, such as Wnt, Notch, TGF-β, and Hedgehog. Nevertheless, CSCs differ from normal stem cells and the bulk of tumor cells in their tumorigenic potential and susceptibility to chemotherapeutic drugs. This may be a possible explanation of the high percentage of cancer recurrence in patients who underwent chemotherapeutic treatment and surgery. This review article focuses on the colorectal cancer stem cell biomarkers and the role of upregulated signaling pathways implicated in the initiation and progression of colorectal cancer.Tumor Biology 02/2015; 36(3). DOI:10.1007/s13277-015-3198-4 · 2.84 Impact Factor