bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒03‒17
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Defining Metabolic Rewiring in Lung Squamous Cell Carcinoma.
  2. Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway.
  3. Association between 18F-FDG uptake in PET/CT, Nrf2, and NQO1 expression and their prognostic significance in non-small cell lung cancer.
  4. A multi-targeted probe-based strategy to identify signaling vulnerabilities in cancers.
  5. Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer.
  6. Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach.
  7. Long non-coding RNA-NEF targets glucose transportation to inhibit the proliferation of non-small-cell lung cancer cells.
  1. Metabolites. 2019 Mar 07. pii: E47. [Epub ahead of print]9(3):
    Defining Metabolic Rewiring in Lung Squamous Cell Carcinoma.
    Paes de Araújo R, Bertoni N, Seneda AL, Felix TF, Carvalho M, Lewis KE, Hasimoto ÉN, Beckmann M, Drigo SA, Reis PP, Mur LAJ.
      Metabolomics based on untargeted flow infusion electrospray ionization high-resolution mass spectrometry (FIE-HRMS) can provide a snap-shot of metabolism in living cells. Lung Squamous Cell Carcinoma (SCC) is one of the predominant subtypes of Non-Small Cell Lung Cancers (NSCLCs), which usually shows a poor prognosis. We analysed lung SCC samples and matched histologically normal lung tissues from eight patients. Metabolites were profiled by FIE-HRMS and assessed using t-test and principal component analysis (PCA). Differentially accumulating metabolites were mapped to pathways using the mummichog algorithm in R, and biologically meaningful patterns were indicated by Metabolite Set Enrichment Analysis (MSEA). We identified metabolic rewiring networks, including the suppression of the oxidative pentose pathway and found that the normal tricarboxylic acid (TCA) cycle were decoupled from increases in glycolysis and glutamine reductive carboxylation. Well-established associated effects on nucleotide, amino acid and thiol metabolism were also seen. Novel aspects in SCC tissue were increased in Vitamin B complex cofactors, serotonin and a reduction of γ-aminobutyric acid (GABA). Our results show the value of FIE-HRMS as a high throughput screening method that could be exploited in clinical contexts.
    Keywords:  flow infusion electrospray ionization high resolution mass spectrometry; lung squamous cell carcinoma; pathways; untargeted metabolites
    DOI:  https://doi.org/10.3390/metabo9030047
  2. Molecules. 2019 Mar 12. pii: E993. [Epub ahead of print]24(5):
    Antrodin C, an NADPH Dependent Metabolism, Encourages Crosstalk between Autophagy and Apoptosis in Lung Carcinoma Cells by Use of an AMPK Inhibition-Independent Blockade of the Akt/mTOR Pathway.
    Yang H, Bai X, Zhang H, Zhang J, Wu Y, Tang C, Liu Y, Yang Y, Liu Z, Jia W, Wang W.
      The current study aims to explore the possible anti-lung carcinoma activity of ADC as well as the underlying mechanisms by which ADC exerts its actions in NSCLC. Findings showed that ADC potently inhibited the viability of SPCA-1, induced apoptosis triggered by ROS, and arrested the cell cycle at the G2/M phase via a P53 signaling pathway. Interestingly, phenomena such as autophagosomes accumulation, conversion of the LC3-I to LC3-II, etc., indicated that autophagy could be activated by ADC. The blockage of autophagy-augmented ADC induced inhibition of cell proliferation, while autophagy activation restored cell death, indicating that autophagy had a protective effect against cell death which was induced by ADC treatment. Meanwhile, ADC treatment suppressed both the Akt/mTOR and AMPK signaling pathways. The joint action of both ADC and the autophagy inhibitor significantly increased the death of SPCA-1. An in vitro phase I metabolic stability assay showed that ADC was highly metabolized in SD rat liver microsomes and moderately metabolized in human liver microsomes, which will assist in predicting the outcomes of clinical pharmacokinetics and toxicity studies. These findings imply that blocking the Akt/mTOR signaling pathway, which was independent of AMPK inhibition, could activate ADC-induced protective autophagy in non-small-cell lung cancer cells.
    Keywords:  AKT; antrodin C; apoptosis; autophagy; mTOR; metabolic stability
    DOI:  https://doi.org/10.3390/molecules24050993
  3. Neoplasma. 2019 Mar 10. pii: 181007N742. [Epub ahead of print]2019
    Association between 18F-FDG uptake in PET/CT, Nrf2, and NQO1 expression and their prognostic significance in non-small cell lung cancer.
    Park SY, Lee SJ, Han JH, Koh YW.
      Two pentose phosphate pathway-related proteins, NF-E2-related factor 2 (Nrf2)/ NAD(P)H dehydrogenase (Quinone) 1 (NQO1) regulate the expression of glucose metabolism and antioxidant genes. We evaluated the prognostic significance of NRF2, NQO1 and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) parameter and their relationship with non-small cell lung cancer (NSCLC) histology. A total of 241 patients, who underwent surgical resection for NSCLC, were reviewed retrospectively. Preoperative 18F-FDG PET and immunohistochemical results of Nrf2 and NQO1 were evaluated. In SQCC, the maximum standardized uptake value (SUVmax) was significantly higher in NQO1-high than in NQO1-low expression (p=0.023). In adenocarcinoma, SUVmax was not correlated with NQO1 expression. Patients with a high NQO1 expression showed poor recurrence-free survival (RFS) and overall survival (OS) than patients with a low NQO1 expression in squamous cell carcinoma (SQCC) (p=0.002 and p=0.014, respectively). NQO1 expression was not associated with clinical outcome in adenocarcinoma. Nrf2 expression was not correlated with prognosis in two types of NSCLC. High SUVmax was associated with poor RFS (p=0.03) but is not related to poor OS (p=0.569) in SQCC. In multivariate analyses, NQO1 expression and SUVmax were not independent prognostic factors in SQCC. However, in multivariate analysis combining NQO1 and SUVmax values, both low SUVmax and low NQO1 was independent prognostic factor for RFS and OS (HR= 3.790, p = 0.033 and HR= 2.961, p = 0.045, respectively). In conclusion, both low SUVmax and low NQO1 was an independent prognostic factor in SQCC alone. The sample size was small but there was a positive correlation between NQO1 expression and SUVmax in SQCC.
    DOI:  https://doi.org/10.4149/neo_2018_181007N742
  4. J Biol Chem. 2019 Mar 11. pii: jbc.RA118.006805. [Epub ahead of print]
    A multi-targeted probe-based strategy to identify signaling vulnerabilities in cancers.
    Rao S, Du G, Hafner M, Subramanian K, Sorger PK, Gray NS.
      Most cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this paper we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multi-targeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof-of-concept, we applied this approach to a KRAS-dependent non-small cell lung cancer (NSCLC) cell line, H23-KRASG12C. Using a combination of phenotypic screens, signaling analyses and kinase inhibitors, we found that dual -inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multi-targeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependencies in cancer. We propose that the strategy described here is complementary to existing genetic-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.
    Keywords:  cancer biology; cancer therapy; cell signaling; chemical biology; chemical probe; drug discovery; kinase signaling; multi-targeting; polypharmacology; receptor tyrosine kinase; small molecule
    DOI:  https://doi.org/10.1074/jbc.RA118.006805
  5. J Exp Clin Cancer Res. 2019 Mar 15. 38(1): 129
    Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer.
    Huang Q, Wang Q, Li D, Wei X, Jia Y, Zhang Z, Ai B, Cao X, Guo T, Liao Y.
      BACKGROUND: Non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. Activation of EGFR signal pathway increased monounsaturated fatty acids (MUFA) and lipid metabolism key enzyme Stearoyl-CoA Desaturase 1 (SCD1) expression. However the correlation between EGFR-TKI resistance and lipid metabolism remains to be determined.METHODS: In this study the differences in lipid synthesis between paired TKI-sensitive and TKI-resistant patient tissues and NSCLC cell lines were explored. Oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) was used to simulate a high lipid metabolic environment and detected the affection on the cytotoxic effect of TKIs (Gefitinib and osimertinib) in cell lines with EGFR-activating mutations. (20S)-Protopanaxatriol (g-PPT), an aglycone of ginsenosides, has been reported to be an effective lipid metabolism inhibitor, was used to inhibit lipid metabolism. Additionally, synergism in cytotoxic effects and signal pathway activation were evaluated using CCK-8 assays, Western blotting, flow cytometry, Edu assays, plate clone formation assays and immunofluorescence. Furthermore, two xenograft mouse models were used to verify the in vitro results.
    RESULTS: Gefitinib-resistant cells have higher lipid droplet content and SCD1 expression than Gefitinib-sensitive cells in both NSCLC cell lines and patient tissues. Additionally oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) abrogates the cytotoxic effect of both Gefitinib and osimertinib in cell lines with EGFR-activating mutations. As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of SCD1 in lung adenocarcinoma cells, and then down-regulated the content of intracellular lipid droplets. Combined treatment with Gefitinib and g-PPT reverses the resistance to Gefitinib and inhibits the activation of p-EGFR and the downstream signaling pathways.
    CONCLUSIONS: Our findings uncover a link between lipid metabolic reprogramming and EGFR-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance.
    Keywords:  EGFR-TKI resistance; Lipid droplet; Lipid metabolism; NSCLC; Oleic acid; SCD1
    DOI:  https://doi.org/10.1186/s13046-019-1120-4
  6. Metabolites. 2019 Mar 13. pii: E50. [Epub ahead of print]9(3):
    Delta-Tocotrienol Modulates Glutamine Dependence by Inhibiting ASCT2 and LAT1 Transporters in Non-Small Cell Lung Cancer (NSCLC) Cells: A Metabolomic Approach.
    Rajasinghe LD, Hutchings M, Gupta SV.
      The growth and development of non-small cell lung cancer (NSCLC) primarily depends on glutamine. Both glutamine and essential amino acids (EAAs) have been reported to upregulate mTOR in NSCLC, which is a bioenergetics sensor involved in the regulation of cell growth, cell survival, and protein synthesis. Seen as novel concepts in cancer development, ASCT2 and LAT transporters allow glutamine and EAAs to enter proliferating tumors as well as send a regulatory signal to mTOR. Blocking or downregulating these glutamine transporters in order to inhibit glutamine uptake would be an excellent therapeutic target for treatment of NSCLC. This study aimed to validate the metabolic dysregulation of glutamine and its derivatives in NSCLC using cellular 1H-NMR metabolomic approach while exploring the mechanism of delta-tocotrienol (δT) on glutamine transporters, and mTOR pathway. Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment. Inhibition of glutamine transporters (ASCT2 and LAT1) and mTOR pathway proteins (P-mTOR and p-4EBP1) was evident in Western blot analysis in a dose-dependent manner. Our findings suggest that δT inhibits glutamine transporters, thus inhibiting glutamine uptake into proliferating cells, which results in the inhibition of cell proliferation and induction of apoptosis via downregulation of the mTOR pathway.
    Keywords:  ASCT2; SLC1A5; alanine; apoptosis; bio actives; cancer; cell growth; cell transporters; essential amino acids; glutamate; glutaminolysis; glutathione; lung; mTOR; nutraceuticals; tocotrienols; vitamin E
    DOI:  https://doi.org/10.3390/metabo9030050
  7. Oncol Lett. 2019 Mar;17(3): 2795-2801
    Long non-coding RNA-NEF targets glucose transportation to inhibit the proliferation of non-small-cell lung cancer cells.
    Chang L, Xu W, Zhang Y, Gong F.
      Long non-coding RNA (lncRNA)-NEF is a newly discovered lncRNA, which exhibits an inhibitory function on the metastasis of hepatocellular carcinoma, while its involvement in other types of malignancy are unknown. In the present study, tumor and adjacent healthy tissues were obtained from patients with non-small-cell lung cancer (NSCLC), and blood was obtained from patients with NSCLC and healthy individuals. Expression levels of lncRNA-NEF in tumor tissue samples, healthy tissue samples and serum were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Receiver operating characteristic curve analysis and survival curve analysis were performed to evaluate the diagnostic and prognostic value of serum lncRNA-NEF for NSCLC. The effects of lncRNA-NEF overexpression in NSCLC cell lines on tumor cell proliferation, glucose uptake, glucose transporter 1 (GLUT1) protein expression and mRNA expression were investigated by Cell Counting kit-8 assay, glucose uptake assay, western blot analysis and RT-qPCR, respectively. It was identified that lncRNA-NEF was downregulated in NSCLC tissues, compared with healthy controls, and the serum level of lncRNA-NEF was negatively associated with primary tumor stage. Therefore, serum lncRNA-NEF may be a sensitive diagnostic and prognostic marker for NSCLC. Overexpression of lncRNA-NEF inhibited NSCLC cell proliferation and glucose uptake, and downregulated GLUT1 expression. Therefore, it can be concluded that lncRNA-NEF can target glucose transportation to inhibit the proliferation of NSCLC cells.
    Keywords:  glucose transporter 1; glucose uptake; long non-coding RNA-NEF; non-small cell lung cancer
    DOI:  https://doi.org/10.3892/ol.2019.9919
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