bims-meluca Biomed news
on Metabolism of non-small cell lung carcinoma
Issue of 2018‒12‒16
twelve papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Lung Cancer. 2018 Dec;pii: S0169-5002(18)30600-7. [Epub ahead of print]126 32-40
    Meijer TWH, Peeters WJM, Dubois LJ, van Gisbergen MW, Biemans R, Venhuizen JH, Span PN, Bussink J.
      PURPOSE: Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology.MATERIALS AND METHODS: Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1.5 mM). Cells were irradiated with 0, 4 or 8 Gy. Cell growth of H2B-mCherry transduced cells and cytotoxicity (CellTox™ Green Cytotoxicity Assay) were measured using live cell imaging (IncuCyte). Inhibitory effects on metabolic profiles was determined using the Seahorse XF96 extracellular Flux analyzer.
    RESULTS: NSCLC cell lines responded differently to glycolysis (lonidamine) and/or glutaminase (968) inhibition, largely corresponding with changes in glycolytic and mitochondrial metabolism upon treatment. Response patterns were not related to histology. 968 was cytotoxic in cell lines with high glutaminase C expression (H1975 and H520), whereas combination treatment was cytotoxic in KRAS mutated cell lines SW900 and H23. H292 and HCC827 were resistant to combination treatment. Treatment with 968 and especially lonidamine resulted in radiosensitization of H292 and HCC827 in terms of decreased relative cell growth and increased cytotoxicity.
    CONCLUSION: NSCLC is a heterogeneous disease, which is reflected in the response of different cell lines to the treatment (combinations) reported here. Only a part of NSCLC patients may benefit from the combination of radiation therapy and metabolic inhibition, making stratification necessary.
    Keywords:  Glutamine metabolism; Glycolysis; Metabolic inhibition; Non-small cell lung cancer; Radiotherapy
    DOI:  https://doi.org/10.1016/j.lungcan.2018.10.016
  2. Cancers (Basel). 2018 Dec 08. pii: E499. [Epub ahead of print]10(12):
    Arif T, Paul A, Krelin Y, Shteinfer-Kuzmine A, Shoshan-Barmatz V.
      Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual "tumour" showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target.
    Keywords:  VDAC1; cancer stem cells; differentiation; mitochondria; si-RNA
    DOI:  https://doi.org/10.3390/cancers10120499
  3. Oncogene. 2018 Dec 07.
    Nishimura T, Nakata A, Chen X, Nishi K, Meguro-Horike M, Sasaki S, Kita K, Horike SI, Saitoh K, Kato K, Igarashi K, Murayama T, Kohno S, Takahashi C, Mukaida N, Yano S, Soga T, Tojo A, Gotoh N.
      Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)-the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib, caused by elevated expression of components of the β-catenin pathway, exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in these gefitinib-resistant cancer cells. Moreover, overexpression of MTHFD2 in gefitinib-sensitive lung cancer cells conferred resistance to gefitinib. Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.
    DOI:  https://doi.org/10.1038/s41388-018-0589-1
  4. Lung Cancer. 2018 Dec;pii: S0169-5002(18)30606-8. [Epub ahead of print]126 89-96
    Ung MH, MacKenzie TA, Onega TL, Amos CI, Cheng C.
      OBJECTIVES: To measure the association between statin exposure and mortality in lung cancer patients belonging to different categories of histological subtype.MATERIALS AND METHODS: A cohort of 19,974 individuals with incident lung cancer between 2007 and 2011 was identified using the SEER-Medicare linked database. Statin exposure both pre- and post-diagnosis was analyzed to identify a possible association with cancer-specific mortality in patients stratified by histological subtype. Intention-to-treat analyses and time-dependent Cox regression models were used to calculate hazard ratios and 95% confidence intervals (95% CIs) corresponding to statin exposure both pre- and post-diagnosis, respectively.
    RESULTS: Overall baseline statin exposure was associated with a decrease in mortality risk for squamous-cell carcinoma patients (HR = 0.89, 95% CI = 0.82-0.96) and adenocarcinoma patients (HR = 0.87, 95% CI = 0.82-0.94), but not among those with small-cell lung cancer. Post-diagnostic statin exposure was associated with prolonged survival in squamous-cell carcinoma patients (HR = 0.68, 95% CI = 0.59-0.79) and adenocarcinoma patients (HR = 0.78, 95% CI = 0.68-0.89) in a dose-dependent manner.
    CONCLUSION: There is consistent evidence indicating that baseline or post-diagnostic exposure to simvastatin and atorvastatin is associated with extended survival in non-small-cell lung cancer subtypes. These results warrant further randomized clinical trials to evaluate subtype-specific effects of certain statins in patient cohorts with characteristics similar to those examined in this study.
    Keywords:  Adenocarcinoma; Histological subtypes; Lung cancer; Retrospective cohort study; SEER-medicare; Small-cell lung cancer; Squamous-cell carcinoma; Statins; Survival analysis
    DOI:  https://doi.org/10.1016/j.lungcan.2018.10.022
  5. Toxicol Appl Pharmacol. 2018 Dec 05. pii: S0041-008X(18)30540-4. [Epub ahead of print]
    Cho HY, Miller-DeGraff L, Blankenship-Paris T, Wang X, Bell DA, Lih F, Deterding L, Panduri V, Morgan DL, Yamamoto M, Reddy AJ, Talalay P, Kleeberger SR.
      Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidant-induced acute injury, wild-type (Nrf2+/+) and Nrf2-deficient (Nrf2-/-) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxia-induced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2+/+ mice but not in Nrf2-/- mice. SFN upregulated a large cluster of basal lung genes that are involved in mitochondrial oxidative phosphorylation, energy metabolism, and cardiovascular protection only in Nrf2+/+ mice. Bioinformatic analysis elucidated ARE-like motifs on these genes. Transcript abundance of the mitochondrial machinery genes remained significantly higher after hyperoxia exposure in SFN-treated Nrf2+/+ mice than in SFN-treated Nrf2-/- mice. Nuclear factor-κB was suggested to be a central molecule in transcriptome networks affected by SFN. Minor improvement of hyperoxia-caused lung histopathology and neutrophilia by SFN in Nrf2-/- mice implies Nrf2-independent or alternate effector mechanisms. SFN is suggested to be as a preventive intervention in a preclinical model of acute lung injury by linking mitochondria and Nrf2. Administration of SFN alleviated acute lung injury-like pathogenesis in a Nrf2-dependent manner. Potential AREs in the SFN-inducible transcriptome for mitochondria bioenergetics provided a new insight into the downstream mechanisms of Nrf2-mediated pulmonary protection.
    Keywords:  Antioxidant response element; Broccoli; Hyperoxia; Lung; Microarray
    DOI:  https://doi.org/10.1016/j.taap.2018.12.004
  6. J Cancer Res Ther. 2018 Dec;14(Supplement): S985-S992
    Rui Y, Wang D, Hu D, Huang L.
      Purpose: To investigate the effects of dalteparin sodium on the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and hypoxia-inducible factor 1α (HIF-1α) in A549 human lung cancer (LC) cell line and a human A549-grafted nude mouse model.Materials and Methods: A549 human lung adenocarcinoma cell line was divided into control group, treated using normal saline (NS); and dalteparin sodium groups, receiving 5, 15, 50, and 150 IU/ml of dalteparin sodium, respectively. Human A549-grafted nude mouse was induced through subcutaneous (SC) injection of A549 (5 × 106/0.2 ml) into the right armpit, and randomly assigned into control group (n = 6) receiving intraperitoneal (i.p.) injection of NS, cisplatin (DDP) group (n = 6, 3 mg/kg DDP alone, i.p., for 3 days), low molecular weight heparin (LMWH) group (n = 6) receiving SC injection of 1500 IU/kg dalteparin sodium for 35 days, and DDP plus LMWH group (n = 6, 3 mg/kg DDP, i.p., for 3 days, followed by SC injection of 1500 IU/kg dalteparin sodium for 35 days).
    Results: Significant difference was noted in the messenger RNA expression of VEGF, VEGFR, and HIF-1α after treating with heparin with a concentration of 15, 50, or 150 IU/ml in the A549 cell line at 24 and 48 h, respectively. In the human A549-grafted nude mouse model, a significant reduction was noted in the expression of VEGF, VEGFR, and HIF-1α in the tumor mass harvested from the mice receiving administration of dalteparin sodium plus DDP.
    Conclusion: Dalteparin sodium had the inhibitory effects on the growth of human LC A549 cells in vitro and A549 LC xenograft model, which could be enhanced when administrated together with DDP.
    Keywords:  Dalteparin sodium; hypoxia-inducible factor-1α; nonsmall cell lung cancer; nude mice; vascular endothelial growth factor
    DOI:  https://doi.org/10.4103/0973-1482.192765
  7. Nucl Med Mol Imaging. 2018 Dec;52(6): 453-461
    Choi S, Kwon HR, Cho HY, Pahk K, Lee SH, Chung JH, Kwon HW, Kim S.
      Purpose: This study aimed to investigate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG), which are volume-based PET parameters, using 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with surgically resectable lung adenocarcinoma.Methods: We retrospectively evaluated 149 patients with lung adenocarcinoma who underwent 18F-FDG PET/CT before surgical resection. Maximum standardized uptake value (SUVmax), MTV, and TLG of the primary tumor with threshold value of SUVmax 30, 40, and 50% were calculated, respectively. To compare the predictive performance of volume-based PET parameters, recurrence-free survival was assessed using the Kaplan-Meier method.
    Results: The study included 70 males and 79 females with an average age of 65.8 years. The median follow-up time was 45.4 months. Recurrence was observed in 53 patients (35.6%). The mean ± SD SUVmax, MTV30%, and TLG30% of the entire cohort were 4.79 ± 2.94, 19.45 ± 24.85, and 56.43 ± 101.88, respectively. The cut-off values of MTV30% and TLG30% for recurrence were 11.07 ad 30.56, respectively. The 1-year recurrence-free survival (RFS) rate was 96.5% in low-MTV30% patients compared with 86.2% in high-MTV30% patients (p = 0.018) and 96.0% in low-TLG30% patients compared with 88.5% in high-TLG30% patients (p < 0.001). On univariate and multivariate analysis, TLG30% (HR, 2.828, p < 0.001; HR, 2.738, p < 0.001, respectively) was an independent prognostic factor for predicting recurrence-free survival (RFS).
    Conclusion: TLG30% value was observed to be a significant prognostic factor for RFS in patients with lung adenocarcinoma treated by surgical resection.
    Keywords:  FDG PET/CT; Lung adenocarcinoma; Metabolic tumor volume; Recurrence; Total lesion glycolysis
    DOI:  https://doi.org/10.1007/s13139-018-0555-4
  8. BMC Cancer. 2018 Dec 10. 18(1): 1238
    Ng Kee Kwong F, Nicholson AG, Pavlidis S, Adcock IM, Chung KF.
      BACKGROUND: COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC).METHODS: Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a ≥ 2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue.
    RESULTS: The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p < 0.05).
    CONCLUSION: PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.
    Keywords:  Lung cancer; Mitochondrion; PGAM5 macrophage; Patient survival
    DOI:  https://doi.org/10.1186/s12885-018-5140-9
  9. Mol Clin Oncol. 2018 Dec;9(6): 640-646
    Himuro N, Niiya Y, Minakata T, Oshima Y, Kataoka D, Yamamoto S, Suzuki T, Kadokura M.
      The expression levels of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil-based chemotherapy in patients with cancer. We herein investigated the differences in the mRNA levels of these enzymes in non-small-cell lung cancer (NSCLC) and evaluated their prognostic value for NSCLC treated by surgical resection. The intratumoral mRNA levels of TP, DPD, TS, and OPRT were quantified in 66 patients with pathological stage I and II NSCLC (adenocarcinoma or squamous cell carcinoma) following complete resection according to the Danenberg Tumor Profile method. The TP level was the only significant prognostic factor for disease-specific survival (DSS) following complete resection; the mean TP mRNA level differed significantly between the high and low mRNA expression groups. The DSS at 5 years was significantly higher in the low TP mRNA compared with that in the high TP mRNA expression group (83.4 vs. 58.6%, respectively; P=0.005). A Cox proportional hazards model revealed that pathological stage, sex, and TP expression were independent prognostic factors for DSS in patients with stage I and II NSCLC following complete resection. Thus, TP level may be used to monitor treatment efficacy and predict the outcome of NSCLC patients.
    Keywords:  Danenberg tumor profile method; complete resection; non-small-cell lung cancer; prognostic factor; thymidine phosphorylase
    DOI:  https://doi.org/10.3892/mco.2018.1726
  10. J Cell Physiol. 2018 Dec 13.
    Liu Y, Wu L, Li K, Liu F, Wang L, Zhang D, Zhou J, Ma X, Wang S, Yang S.
      The incidence and mortality of lung cancer ranked the first among all types of cancer in China, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for 85% of all lung cancers. Given that the survival rate of patients with advanced NSCLC is still poor nowadays, identification of novel therapeutic targets and the development of effective therapies are desired for the treatment of NSCLC in clinics. In this study, we reported the upregulation of ornithine aminotransferase (OAT) in NSCLC cells and clinical tumor samples as well as its association with the advanced TNM stage, metastasis, and poor tumor differentiation of lung cancer. Using different NSCLC cell lines, we demonstrated that OAT promoted the proliferation, invasion, and migration, inhibited the apoptosis, and altered cell cycle of NSCLC cells; besides, the involvement of OAT-miR-21-glycogen synthase kinase-3β signaling in the functional role of OAT in NSCLC was also revealed. Importantly, in the absence of OAT, the growth and metastasis of tumor lung cancer xenograft was significantly suppressed in the nude mice. Based on our findings, OAT may be a potential novel biomarker for the diagnosis and therapeutic outcome monitoring of NSCLC. Inhibition of OAT may also represent a new therapeutic strategy of NSCLC.
    Keywords:  GSK-3β; invasion and migration; miR-21; non-small cell lung cancer; ornithine aminotransferase; proliferation
    DOI:  https://doi.org/10.1002/jcp.27939
  11. Oncol Lett. 2018 Dec;16(6): 7074-7081
    Chen J, Zhang L, Yu X, Zhou H, Luo Y, Wang W, Wang L.
      Alterations of mitochondrial DNA (mtDNA) have been identified in several types of solid tumor. However, to the best of our knowledge, the clinical significance of plasma mtDNA content in lung cancer remains unknown. Thus, the current study explored the diagnostic and prognostic value of plasma mtDNA quantification in patients with lung cancer. Plasma mtDNA copy numbers of patients with lung cancer (n=128) and healthy individuals (n=107) were quantified by quantitative polymerase chain reaction. Plasma mtDNA copy numbers in patients and healthy controls were 0.89×104 and 1.37×104 copies/µl, respectively (P<0.0001). Furthermore, lower plasma mtDNA content was associated with tumor size, lymph node metastases, distant metastases and serum carcinoembryonic antigen levels (P<0.05), but was not associated with pathological type, age, sex or main driver gene mutation status (P>0.05). Plasma mtDNA facilitated the detection of lung cancer at a threshold of 1.19×104 copies/µl with a sensitivity of 71.1% and specificity of 70.1%, as determined by receiver operating characteristic curve analysis. Advanced stage (III and IV) patients with a lower mtDNA copy number (cutoff: 1.02×104 copies/µl) tended to exhibit poorer prognosis (P<0.05). These results indicated that plasma mtDNA content is a promising and complementary candidate with tissue mtDNA for diagnosis and prognostic prediction for lung cancer.
    Keywords:  diagnosis; lung cancer; mitochondrial DNA; prognosis; quantitative polymerase chain reaction
    DOI:  https://doi.org/10.3892/ol.2018.9515