bims-meluca Biomed news
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒01‒13
six papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Int J Mol Sci. 2019 Jan 10. pii: E252. [Epub ahead of print]20(2):
    Vanhove K, Derveaux E, Graulus GJ, Mesotten L, Thomeer M, Noben JP, Guedens W, Adriaensens P.
      Lung cancer cells are well-documented to rewire their metabolism and energy production networks to support rapid survival and proliferation. This metabolic reorganization has been recognized as a hallmark of cancer. The increased uptake of glucose and the increased activity of the glycolytic pathway have been extensively described. However, over the past years, increasing evidence has shown that lung cancer cells also require glutamine to fulfill their metabolic needs. As a nitrogen source, glutamine contributes directly (or indirectly upon conversion to glutamate) to many anabolic processes in cancer, such as the biosynthesis of amino acids, nucleobases, and hexosamines. It plays also an important role in the redox homeostasis, and last but not least, upon conversion to α-ketoglutarate, glutamine is an energy and anaplerotic carbon source that replenishes tricarboxylic acid cycle intermediates. The latter is generally indicated as glutaminolysis. In this review, we explore the role of glutamine metabolism in lung cancer. Because lung cancer is the leading cause of cancer death with limited curative treatment options, we focus on the potential therapeutic approaches targeting the glutamine metabolism in cancer.
    Keywords:  Lung cancer; glutamine; glutaminolysis; metabolism; pathways; targeted treatment
    DOI:  https://doi.org/10.3390/ijms20020252
  2. Clin Lung Cancer. 2018 Dec 19. pii: S1525-7304(18)30335-8. [Epub ahead of print]
    Vernieri C, Signorelli D, Galli G, Ganzinelli M, Moro M, Fabbri A, Tamborini E, Marabese M, Caiola E, Broggini M, Hollander L, Gallucci R, Vandoni G, Gavazzi C, Triulzi T, Colombo MP, Rizzo AM, Corsetto PA, Pruneri G, de Braud F, Sozzi G, Torri V, Garassino MC.
      Advanced lung adenocarcinoma with inactive liver kinase B1 (LKB1) tumor suppressor protein is associated with poor response to immune checkpoint inhibitors and molecularly targeted agents, and with dismal patient prognosis. LKB1 is a central orchestrator of cancer cell metabolism, and halts tumor growth/proliferation during metabolic stress. Recent preclinical evidence suggests that LKB1-inactive lung adenocarcinoma is highly sensitive to metformin, a safe and low-cost antidiabetic compound that inhibits mitochondrial oxidative phosphorylation. The effects of metformin can be enhanced by nutrient deprivation (ie, glucose, amino acids), which reduces intracellular levels of ATP and anabolic precursors and can be achieved by the fasting mimicking diet (FMD). Noticeably, metformin also prevents resistance to cisplatin in preclinical in vitro and in vivo models of LKB1-inactive lung adenocarcinoma. Based on such preclinical evidence, the phase II FAME trial was designed to test the hypothesis that the addition of metformin, with or without cyclic FMD, to standard platinum-based chemotherapy improves the progression-free survival of patients with advanced, LKB-1 inactive lung adenocarcinoma. Enrolled patients will be randomized in a 1:1 ratio to receive cisplatin/carboplatin and pemetrexed with the addition of metformin alone (Arm A) or metformin plus FMD (Arm B). The FAME study will use a "pick-the-winner" design with the aim of establishing which of the 2 experimental treatments is superior in terms of antitumor efficacy and safety. The primary assumption of the study is that the combination of the 2 experimental treatments shall improve median progression-free survival from 7.6 months (historical data with chemotherapy alone) to 12 months. Secondary study endpoints are: objective response rate, overall survival, treatment tolerability, and compliance to the experimental treatment.
    Keywords:  Cancer metabolism; LKB1 inactivation; Overall survival; Progression-free survival; Safety
    DOI:  https://doi.org/10.1016/j.cllc.2018.12.011
  3. J Exp Clin Cancer Res. 2019 Jan 06. 38(1): 5
    Hung PF, Hong TM, Chang CC, Hung CL, Hsu YL, Chang YL, Wu CT, Chang GC, Chan NL, Yu SL, Yang PC, Pan SH.
      BACKGROUND: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis.METHODS: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients.
    RESULTS: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients.
    CONCLUSIONS: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.
    Keywords:  Hypoxia; Lung cancer; Metastasis; SUMOylation; Slug
    DOI:  https://doi.org/10.1186/s13046-018-0996-8
  4. Cell. 2018 Dec 28. pii: S0092-8674(18)31563-0. [Epub ahead of print]
    Liu S, Hausmann S, Carlson SM, Fuentes ME, Francis JW, Pillai R, Lofgren SM, Hulea L, Tandoc K, Lu J, Li A, Nguyen ND, Caporicci M, Kim MP, Maitra A, Wang H, Wistuba II, Porco JA, Bassik MC, Elias JE, Song J, Topisirovic I, Van Rechem C, Mazur PK, Gozani O.
      Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
    Keywords:  METTL13; RAS; eEF1A; lung cancer; lysine methylation; pancreatic cancer; protein methylation; translation; translation elongation
    DOI:  https://doi.org/10.1016/j.cell.2018.11.038
  5. Trends Endocrinol Metab. 2019 Jan 07. pii: S1043-2760(18)30226-1. [Epub ahead of print]
    Fang Y, Tang S, Li X.
      Sirtuins are highly conserved NAD+-dependent enzymes that are capable of removing a wide range of lipid lysine acyl-groups from protein substrates in a NAD+-dependent manner. These NAD+-dependent activities enable sirtuins to monitor cellular energy status and modulate gene transcription, genome stability, and energy metabolism in response to environmental signals. Consequently, sirtuins are important for cell survival, stress resistance, proliferation, and differentiation. In recent years, sirtuins are increasingly recognized as crucial regulators of stem cell biology in addition to their well-known roles in metabolism and aging. This review article highlights our current knowledge on sirtuins in stem cells, including their functions in pluripotent stem cells, embryogenesis, and development as well as their roles in adult stem cell maintenance, regeneration, and aging.
    Keywords:  embryonic development; epigenetics; metabolism; regenerative capacity; sirtuins
    DOI:  https://doi.org/10.1016/j.tem.2018.12.002
  6. Int J Mol Sci. 2019 Jan 09. pii: E244. [Epub ahead of print]20(2):
    Hsieh KY, Wei CK, Wu CC.
      Tissue factor (TF) expressed in cancer cells has been linked to tumor-associated thrombosis, a major cause of mortality in malignancy. Hypoxia is a common feature of solid tumors and can upregulate TF. In this study, the effect of YC-1, a putative inhibitor of hypoxia-inducible factor-1α (HIF-1α), on hypoxia-induced TF expression was investigated in human lung cancer A549 cells. YC-1 selectively prevented hypoxia-induced TF expression and procoagulant activity without affecting the basal TF levels. Surprisingly, knockdown or pharmacological inhibition of HIF-1α failed to mimic YC-1's effect on TF expression, suggesting other mechanisms are involved. NF-κB, a transcription factor for TF, and its upstream regulator p38, were activated by hypoxia exposure. Treatment of hypoxic A549 cells with YC-1 prevented the activation of both NF-κB and p38. Inhibition of p38 suppressed hypoxia-activated NF-κB, and inhibited TF expression and activity to similar levels as treatment with an NF-κB inhibitor. Furthermore, stimulation of p38 by anisomycin reversed the effects of YC-1. Taken together, our results suggest that YC-1 prevents hypoxia-induced TF in cancer cells by inhibiting the p38/NF-κB pathway, this is distinct from the conventional anticoagulants that systemically inhibit blood coagulation and may shed new light on approaches to treat tumor-associated thrombosis.
    Keywords:  MAP kinases; cancer; hypoxia; procoagulant activity; tissue factor
    DOI:  https://doi.org/10.3390/ijms20020244