NMR (1H and 13C) based signatures of abnormal choline metabolism in oral squamous cell carcinoma with no prominent Warburg effect

Bag, Swarnendu; Banerjee, Deb Ranjan; Basak, Amit; Das, Amit Kumar; Pal, Mousumi; Banerjee, Rita; Paul, Ranjan Rashmi; Chatterjee, Jyotirmoy

doi:10.1016/j.bbrc.2015.02.149

Cited by 34 publications

(23 citation statements)

References 18 publications

(32 reference statements)

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“…The decrease in choline compounds caused by DEK could indicate their increased incorporation into membranes or could be due to increased choline breakdown. While choline compounds are generally increased in other cancer types, and are considered biomarkers for breast cancer, we have observed a decrease in choline levels in C-SCC1 cells in line with another NMR study of oral SCC [71]. Therefore, DEK overexpression is sufficient to cause a decrease in choline levels in keratinocytes and SCC cells.…”

Section: Discussionsupporting

confidence: 88%

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

et al. 2017

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The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.

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Section: Discussionsupporting

confidence: 88%

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

et al. 2017

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“…39 Malate and oxaloacetate (OAA), the TCA cycle intermediates, are main raw materials for the lipid (especially TG, PG, DAG, and PI) biosynthesis. 32 Again, MS/MS fragmentation of well separated metabolites would further enrich available metabolomic database ( Fig. 39,40 Present study has also depicted the up-regulation of lipid anabolism rather than passing through the normal TCA cycles (Fig.…”

Section: Discussionmentioning

confidence: 73%

“…2,28,38 Therefore, both glycolytic ux as well as de novo biosynthesis of lipids, nucleotides and non-essential amino acids is crucial for cancer cell proliferation. 32 Here another choline derivative, PC was up-regulated in cancer (Table 2). These are very essential for membrane biogenesis for newly dividing cells.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 To facilitate the metabolite identication and quantication study different commercially available advanced instrument like quadrupole-time-of-ight (QTOF), nano liquid chromatography (nanoLC), gas chromatography (GC) are connected additionally with different mass analyser for the online separation of crude sample and to give spectra at lower range which are the possible range for different metabolites and lipid molecules. 32 The study elucidated an altered metabolic pathway in cancer by qualitative assessment and identication of NMR peak from HMDB database. 26 Nano liquid chromatography (nanoLC) coupled MALDI allows to separate sample components such as metabolites and small molecules with the help of C 18 reverse phase columns prior to MALDI MS or MS/MS analysis.…”

Section: Introductionmentioning

confidence: 99%

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NanoLC MALDI MS/MS based quantitative metabolomics reveals the alteration of membrane biogenesis in oral cancer

et al. 2016

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Cancer cells use aberrant metabolic process for proliferation and metastasis. High-throughput separation and quantification of metabolites from bio-samples is crucial in this aspect. Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS), a prime technique used for metabolite identifications, suffers from several limitations in quantification studies. In this study, we have established a novel approach using conventional nanoLC-MALDI MS/MS interface for separation, identification and label free quantifications of the metabolites from biopsies. Quantification of metabolite using MALDI requires a homogeneous distribution of the matrix mixed samples on target plate for proportional time-of-flight (ToF) with the concentration of a particular metabolite present in that sample under same laser intensity.Here, crude metabolites extracted from cancer biopsies are separated and eluted as 'fraction spots' on MALDI target plate using nanoLC. Introducing a novel parameter, %aAUC (percentage of average area under the curve), comparative quantification of separated metabolites isolated from normal, pre-cancer and cancer biopsies has been explored. Such comparative quantification is only possible with multiple AUCs of a particular metabolite obtained from this nanoLC-MALDI MS approach. Further, selected metabolite peaks have been analyzed through MS/MS fragmentation. This approach was validated using known concentrations of an internal standard (thiourea) with its corresponding aAUC (average area under the curve). Interestingly, such comparative quantification has revealed a significant change in expression of crucial lipid metabotypes like triglyceride, phospatidyl inositol, phosphatidyl choline, glycerophospholipid, cytidine diphosphate-diacylglycerol and phosphatidylinositol bisphosphate indicating altered lipid metabolism associated membrane biogenesis in oral pre-cancer (oral submucous fibrosis) and cancer. Hence, our study successfully established an altered membrane biogenesis in oral cancer using a novel and distinct approach for separation, identification and label-free quantification of metabolites in fast growing metabotype-biomarker identification era.

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“…Metabolomics represent a promising approach for the discovery of novel targets and biomarkers in head and neck squamous cell carcinoma [10]. Previous NMR-based serum metabolomics studies revealed the levels of glutamine, propionate, acetone, and choline accurately differentiated patients with OSCC from healthy controls, with an area under the receiver operating characteristic curve (AUC) of 0.97 [20]. Gupta et al reported another NMR-based metabolic fingerprint obtained for OSCC, which was significant even at the leukoplakia stage, with the four biomarkers (glutamine, acetone, acetate, and choline) achieving an AUC of 0.96 and an accuracy of 92.4% [21].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma

Tsai

Lin

Kang

et al. 2020

JCM

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Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC were investigated through 600-MHz nuclear magnetic resonance (NMR) metabolomics analysis. We found that the levels of creatine, creatine phosphate, glycine, and tyramine in plasma significantly decreased in stage IV ENE positive OSCC compared with stage IV ENE negative OSCC. To understand the underlying mechanism behind the alteration of plasma metabolites, our tissue analysis revealed that the carnitine level significantly increased in tumors but significantly decreased in the adjacent normal tissue in advanced stage OSCC, in addition to decreased levels of alanine and pyruvate in tumor tissues. The global metabolomics analysis on tumor tissues also showed that stage IV tumors with an ENE positive status demonstrated higher levels of aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose but lower levels of alanine, choline, glucose, isoleucine, lactate, leucine, myo-inositol, O-acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine than tumors with an ENE negative status. We concluded that metabolomics alterations in tumor tissues correspond to an increase in the tumor stage and are detectable in plasma samples. Metabolomic alterations of OSCC can serve as potential diagnostic markers and predictors of ENE in patients with stage IV OSCC.

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NMR (1H and 13C) based signatures of abnormal choline metabolism in oral squamous cell carcinoma with no prominent Warburg effect

Cited by 34 publications

References 18 publications

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

NanoLC MALDI MS/MS based quantitative metabolomics reveals the alteration of membrane biogenesis in oral cancer

Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma

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