bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019–08–04
eleven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Effect of IDH3a on glucose uptake in lung adenocarcinoma: A pilot study based on [18 F]FDG.
  2. Integration of metabolomics and transcriptomics to reveal metabolic characteristics and key targets associated with cisplatin resistance in non-small cell lung cancer.
  3. Analysis of Survival-Related lncRNA Landscape Identifies A Role for LINC01537 in Energy Metabolism and Lung Cancer Progression.
  4. Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex.
  5. Radiosensitizing effects of Cyclocarya paliurus polysaccharide on hypoxic A549 and H520 human non-small cell lung carcinoma cells.
  6. Interleukin-9 promotes tumorigenesis through augmenting angiogenesis in non-small cell lung cancer.
  7. Liquid Biopsy in Lung Cancer Screening: The Contribution of Metabolomics. Results of A Pilot Study.
  8. Therapeutic Targeting of Aldolase A Interactions Inhibits Lung Cancer Metastasis and Prolongs Survival.
  9. Screening miRNAs associated with resistance gemcitabine from exosomes in A549 lung cancer cells.
  10. A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer.
  11. Successful long-term treatment of non-small cell lung cancer positive for RET rearrangement with pemetrexed.
  1. Cancer Med. 2019 Jul 29.
    Effect of IDH3a on glucose uptake in lung adenocarcinoma: A pilot study based on [18 F]FDG.
    Bulin Du, Tong Sun, Xuena Li, Yao Diao, Yaming Li.
      Subunit of isocitrate dehydrogenase 3 (IDH3a) as upstream of the hypoxia-inducible factor was reported highly expressed in malignant tumors, playing an important role in glucose metabolism reprogramming. As one of rate-limiting enzyme in the Krebs cycle, whether high expression of IDH3a affects glucose uptake in tumors has not been elucidated. This study was aimed to investigate the relationship between IDH3a expression and tumor glucose uptake. Sixty-five patients who underwent 2-[18 F]-2-deoxy-D-glucose ([18 F]-FDG) positron emission tomography/computed tomography (PET/CT) imaging before surgery and pathologically diagnosed as lung adenocarcinoma were included. All patients were divided into high (n = 31) and low (n = 34) groups according IDH3a expression by immunohistochemistry. Comparatively higher [18 F]-FDG uptake was found in high IDH3a expression group. Glucose transporter 1 (GLUT1) level was demonstrated to correlate with IDH3a expression, but not for hexokinase 2 (HK2). Furthermore, A549 and H1299 cells experiment showed, the expression of p-AKT and GLUT1 were significantly downregulated after IDH3a interference. The cellular uptake of [18 F]-FDG and lactate production were significantly reduced in treatment group. In summary, high expression of IDH3a in lung adenocarcinoma patients is associated with higher glucose uptake. IDH3a targets AKT-GLUT1 pathway to affect glucose uptake and metabolites in lung adenocarcinoma.
    Keywords:  2-[18F]-2-deoxy-D-glucose; isocitrate dehydrogenase; lung adenocarcinoma; positron emission tomography
    DOI:  https://doi.org/10.1002/cam4.2421
  2. J Proteome Res. 2019 Aug 02.
    Integration of metabolomics and transcriptomics to reveal metabolic characteristics and key targets associated with cisplatin resistance in non-small cell lung cancer.
    Yuhuan Shi, Yuanyuan Wang, Wanying Huang, Yang Wang, Rong Wang, Yongfang Yuan.
      Continuous exposure to cisplatin can induce drug resistance to limit efficacy, however, the underlying mechanisms correlated to cisplatin resistance are still unclear. Drug-sensitive A549 cells and cisplatin-resistant A549/DDP cells were used to explore the potential metabolic pathways and key targets associated with cisplatin resistance by integrating untargeted metabolomics with transcriptomics. Data are available via ProteomeXchange with identifier PXD013265. The results of comprehensive analyses showed that 19 metabolites were significantly changed in A549/DDP vs A549 cells, and some pathways had a close relationship with cisplatin resistance, such as the biosynthesis of aminoacyl-tRNA, glycerophospholipid metabolism, and glutathione metabolism. Moreover, transcriptomics analysis showed glutathione metabolism was also obviously affected in A549/DDP, which indicated that glutathione metabolism played an import role in the process of drug resistance. Meanwhile, transcriptomics analysis suggested the four enzymes related to glutathione metabolism - CD13, GPX4, RRM2B, and OPLAH - as potential targets of cisplatin resistance in NSCLC. Further studies identified the over-expressions of these four enzymes in A549/DDP. The elucidation of mechanism and discovery of new potential targets may help us have a better understanding of cisplatin resistance.
    DOI:  https://doi.org/10.1021/acs.jproteome.9b00209
  3. Int J Mol Sci. 2019 Aug 01. pii: E3713. [Epub ahead of print]20(15):
    Analysis of Survival-Related lncRNA Landscape Identifies A Role for LINC01537 in Energy Metabolism and Lung Cancer Progression.
    Wei Gong, Lei Yang, Yuanyuan Wang, Jianfeng Xian, Fuman Qiu, Li Liu, Mingzhu Lin, Yingyi Feng, Yifeng Zhou, Jiachun Lu.
      Many long non-coding RNAs (lncRNAs) have emerged as good biomarkers and potential therapeutic targets for various cancers. We aimed to get a detailed understanding of the lncRNA landscape that is associated with lung cancer survival. A comparative analysis between our RNA sequencing (RNA-seq) data and TCGA datasets was conducted to reveal lncRNAs with significant correlations with lung cancer survival and then the association of the most promising lncRNA was validated in a cohort of 243 lung cancer patients. Comparing RNA-seq data with TCGA ones, 84 dysregulated lncRNAs were identified in lung cancer tissues, among which 10 lncRNAs were significantly associated with lung cancer survival. LINC01537 was the most significant one (p = 2.95 × 10-6). Validation analysis confirmed the downregulation of LINC01537 in lung cancer. LINC01537 was observed to inhibit tumor growth and metastasis. It also increased cellular sensitivity to nilotinib. PDE2A (phosphodiesterase 2A) was further identified to be a target of LINC01537 and it was seen that LINC01537 promoted PDE2A expression via RNA-RNA interaction to stabilize PDE2A mRNA and thus echoed effects of PDE2A on energy metabolism including both Warburg effect and mitochondrial respiration. Other regulators of tumor energy metabolism were also affected by LINC01537. These results elucidate a suppressed role of LINC01537 in lung cancer development involving tumor metabolic reprogramming, and we believe that it might be a biomarker for cancer survival prediction and therapy.
    Keywords:  LINC01537; PDE2A; energy metabolism; lung cancer; survival
    DOI:  https://doi.org/10.3390/ijms20153713
  4. J Mater Chem B. 2019 Jul 31. 7(30): 4706-4716
    Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex.
    Dan Liu, Angelina Angelova, Jianwen Liu, Vasil M Garamus, Borislav Angelov, Xinlei Zhang, Yawen Li, Guillaume Feger, Na Li, Aihua Zou.
      Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.
    DOI:  https://doi.org/10.1039/c9tb00629j
  5. Int J Mol Med. 2019 Jul 26.
    Radiosensitizing effects of Cyclocarya paliurus polysaccharide on hypoxic A549 and H520 human non-small cell lung carcinoma cells.
    Fengmin Zhang, Bin Fan, Lijun Mao.
      Cyclocarya paliurus (CP) polysaccharide (CPP) is a chemical component contained in CP, which has been reported to possess significant hypoglycemic activity. The present study aimed to investigate the radiosensitizing effect and underlying mechanisms of CPP on hypoxic A549 and H520 human non‑small cell lung carcinoma cells. Cell viability, apoptosis and proliferation were determined using Cell Counting kit‑8 assay, flow cytometry and colony formation assay, respectively. mRNA and protein expression levels were determined by reverse transcription‑quantitative PCR and western blot analysis, respectively. The results suggested that CPP markedly inhibited the viability of hypoxic A549 and H520 cells. In response to combined treatment with CPP and radiation, hypoxic A549 and H520 cells exhibited enhanced apoptosis; in addition, cell proliferation was suppressed and the expression levels of hypoxia‑inducible factor‑1α, survivin and cleaved caspase‑3 were modified. Furthermore, CPP in combination with radiation affected the mammalian target of rapamycin (mTOR)/Akt/phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K) pathway. These findings indicated that CPP may enhance the radiosensitivity of hypoxic A549 and H520 cells; this effect may be associated with inhibition of the mTOR/Akt/PI3K pathway. The potential radiosensitizing effects of CPP on hypoxic A549 and H520 cells suggested that CPP may be an effective target for treatment of non‑small cell lung carcinoma.
    DOI:  https://doi.org/10.3892/ijmm.2019.4289
  6. Int Immunopharmacol. 2019 Jul 25. pii: S1567-5769(19)30685-X. [Epub ahead of print]75 105766
    Interleukin-9 promotes tumorigenesis through augmenting angiogenesis in non-small cell lung cancer.
    Jun He, Li Wang, Chengda Zhang, Wenbin Shen, Yong Zhang, Tao Liu, Haoyue Hu, Xiaoxiao Xie, Feng Luo.
      IL-9 is a proinflammatory cytokine that plays a critical role in autoimmunity and inflammatory diseases. However, its role in tumorigenesis has not been well studied. In this study, we found that IL-9 expression was significantly increased and associated with poor progression in human non-small cell lung cancer (NSCLC). Ectopic expression of IL-9 in NSCLC cells did not affect cell proliferation and apoptosis in vitro, but markedly promoted tumor growth in vivo. Immune-profile analysis showed no significant changes in the frequencies of infiltrated immune cells in the tumor site, neither in nude mice nor in immune-competent mice. However, we found that VEGF and microvessel density (MVD) were significantly increased in xenografts. IL-9 could promote cell growth and tube formation of HUVEC cells in vitro. In addition, correlation analysis implied a significant positive relationship between the density of IL-9 and VEGF, as well as MVD in human NSCLC tissues. Finally, we found that IL-9 stimulated tumor angiogenesis via STAT3 signaling. Together, our findings demonstrate a promoting role of IL-9 in lung cancer development, probably through promoting tumor angiogenesis. IL-9 thus may represent a new prognostic marker and therapeutic target for NSCLC.
    Keywords:  Angiogenesis; Interleukin-9; Non-small cell lung cancer; VEGF
    DOI:  https://doi.org/10.1016/j.intimp.2019.105766
  7. Cancers (Basel). 2019 Jul 29. pii: E1069. [Epub ahead of print]11(8):
    Liquid Biopsy in Lung Cancer Screening: The Contribution of Metabolomics. Results of A Pilot Study.
    Sandeep Singhal, Christian Rolfo, Andrew W Maksymiuk, Paramjit S Tappia, Daniel S Sitar, Alessandro Russo, Parveen S Akhtar, Nazrina Khatun, Parveen Rahnuma, Ahmed Rashiduzzaman, Rashid Ahmed Bux, Guoyu Huang, Bram Ramjiawan.
      Background: Lung cancer is the most common cause of cancer-related deaths worldwide. Early diagnosis is crucial to increase the curability chance of the patients. Low dose CT screening can reduce lung cancer mortality, but it is associated with several limitations. Metabolomics is a promising technique for cancer diagnosis due to its ability to provide chemical phenotyping data. The intent of our study was to explore metabolomic effects and profiles of lung cancer patients to determine if metabolic perturbations in the SSAT-1/polyamine pathway can distinguish between healthy participants and lung cancer patients as a diagnostic and treatment monitoring tool. Patients and Methods: Plasma samples were collected as part of the SSAT1 Amantadine Cancer Study. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and quantify metabolite concentrations in lung cancer patient and control samples. Standard statistical analyses were performed to determine whether metabolite concentrations could differentiate between healthy subjects and lung cancer patients, as well as risk prediction modeling applied to determine whether metabolic profiles could provide an indication of cancer progression in later stage patients. Results: A panel consisting of 14 metabolites, which included 6 metabolites in the polyamine pathway, was identified that correctly discriminated lung cancer patients from controls with an area under the curve of 0.97 (95% CI: 0.875-1.0). Conclusion: When used in conjunction with the SSAT-1/polyamine pathway, these metabolites may provide the specificity required for diagnosing lung cancer from other cancer types and could be used as a diagnostic and treatment monitoring tool.
    Keywords:  NSCLC; SSAT-1; lung cancer; metabolomic fingerprint; metabolomics; polyamine
    DOI:  https://doi.org/10.3390/cancers11081069
  8. Cancer Res. 2019 Jul 29. pii: canres.4080.2018. [Epub ahead of print]
    Therapeutic Targeting of Aldolase A Interactions Inhibits Lung Cancer Metastasis and Prolongs Survival.
    Yu-Chan Chang, Jean Chiou, Yi-Fang Yang, Chia-Yi Su, Yuan-Feng Lin, Chia-Ning Yang, Pei-Jung Lu, Ming-Shyan Huang, Chih-Jen Yang, Michael Hsiao.
      Cancer metabolic reprogramming promotes tumorigenesis and metastasis, however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines in vitro and formation of metastatic lung cancer foci in vivo. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed gamma-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both in vitro and in vivo. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an anti-retroviral agent that targets HIV integrase, as a pharmacological inhibitor of ALDOA-gamma-actin binding that produced anti-metastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with gamma-actin, targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-4080
  9. Cancer Manag Res. 2019 ;11 6311-6321
    Screening miRNAs associated with resistance gemcitabine from exosomes in A549 lung cancer cells.
    Ai-Ling Liang, Shen-Lin Du, Bin Zhang, Jing Zhang, Xuan Ma, Cui-Yun Wu, Yong-Jun Liu.
       Purpose: To establish a gemcitabine-resistant lung adenocarcinoma cell line, A549/G+, and to screen the differences of miRNA expression in exosomes from A549 and A549/G+ cells.
    Methods: A549 cells were exposed in gemcitabine until they were resistant to gemcitabine, and extracted exosomes from A549 and A549/G+. The RNAs from exosomes were subjected to miRNA expression microarray experiments.
    Results: After 39 weeks of continuous induction, we induced drug resistance in A549 cells. The resistance index was 6. Via GeneChip miRNA 4.0 analysis, there were 446 differential miRNAs between A549 and A549/G+. Target gene prediction and pathway analysis discovered the microRNAs in the intersections may participate in drug resistance.
    Conclusion: These differential miRNAs help to do in-depth research to elucidate the mechanism of resistance to gemcitabine in non-small cell lung cancer.
    Keywords:  NSCLC; drug resistance; exosomes; gemcitabine; miRNA; microarray; non-small cell lung cancer
    DOI:  https://doi.org/10.2147/CMAR.S209149
  10. Transl Lung Cancer Res. 2019 Jun;8(3): 247-257
    A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer.
    Takefumi Komiya, Regan M Memmott, Gideon M Blumenthal, Wendy Bernstein, Marc S Ballas, Roopa De Chowdhury, Guinevere Chun, Cody J Peer, William D Figg, David J Liewehr, Seth M Steinberg, Giuseppe Giaccone, Eva Szabo, Shigeru Kawabata, Junji Tsurutani, Arun Rajan, Phillip A Dennis.
       Background: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed.
    Methods: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle.
    Results: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4).
    Conclusions: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).
    Keywords:  Lung cancer; pemetrexed; phase I/II, sirolimus; thymidylate synthase (TS)
    DOI:  https://doi.org/10.21037/tlcr.2019.04.19
  11. Onco Targets Ther. 2019 ;12 5355-5358
    Successful long-term treatment of non-small cell lung cancer positive for RET rearrangement with pemetrexed.
    Masayuki Takeda, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa.
      The discovery of RET rearrangement in non-small cell lung cancer (NSCLC) has prompted development of molecularly targeted therapy for such tumors, with several clinical trials being under way to evaluate the therapeutic effects of multitargeted tyrosine kinase inhibitors. The sensitivity of RET fusion-positive NSCLC to cytotoxic chemotherapy has remained unclear, however. We here report a case of NSCLC positive for the CCDC6-RET fusion gene that benefited from treatment with pemetrexed over a period of 30 months, suggesting that thymidylate synthase-targeted drugs such as pemetrexed may show efficacy for NSCLC harboring RET fusions.
    Keywords:  CCDC6-RET; non–small cell lung cancer; pemetrexed; predictive marker
    DOI:  https://doi.org/10.2147/OTT.S211582
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