bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2021‒04‒04
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism.
  2. Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.
  3. Statins and immunotherapy: Togetherness makes strength The potential effect of statins on immunotherapy for NSCLC.
  4. Metabolic Health Together with a Lipid Genetic Risk Score Predicts Survival of Small Cell Lung Cancer Patients.
  5. Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia.
  1. Cells. 2021 Mar 12. pii: 634. [Epub ahead of print]10(3):
    A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism.
    Padilla J, Lee J.
      BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.
    Keywords:  BTB and CNC homology 1 BACH1; Nrf2 (encoded by Nfe2l2); breast cancer; glycolysis; heme oxygenase 1 (HMOX1); hemin; lung cancer; metformin; mitochondrial electron transport chain (ETC); mitochondrial metabolism
    DOI:  https://doi.org/10.3390/cells10030634
  2. Metabolites. 2021 Mar 26. pii: 198. [Epub ahead of print]11(4):
    Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.
    Piecyk M, Triki M, Laval PA, Dragic H, Cussonneau L, Fauvre J, Duret C, Aznar N, Renno T, Manié SN, Chaveroux C, Ferraro-Peyret C.
      Genetic alterations in non-small cell lung cancers (NSCLC) stimulate the generation of energy and biomass to promote tumor development. However, the efficacy of the translation process is finely regulated by stress sensors, themselves often controlled by nutrient availability and chemotoxic agents. Yet, the crosstalk between therapeutic treatment and glucose availability on cell mass generation remains understudied. Herein, we investigated the impact of pemetrexed (PEM) treatment, a first-line agent for NSCLC, on protein synthesis, depending on high or low glucose availability. PEM treatment drastically repressed cell mass and translation when glucose was abundant. Surprisingly, inhibition of protein synthesis caused by low glucose levels was partially dampened upon co-treatment with PEM. Moreover, PEM counteracted the elevation of the endoplasmic reticulum stress (ERS) signal produced upon low glucose availability, providing a molecular explanation for the differential impact of the drug on translation according to glucose levels. Collectively, these data indicate that the ERS constitutes a molecular crosstalk between microenvironmental stressors, contributing to translation reprogramming and proteostasis plasticity.
    Keywords:  ER stress signaling; NSCLC; glucose availability; pemetrexed; protein synthesis
    DOI:  https://doi.org/10.3390/metabo11040198
  3. Cancer Rep (Hoboken). 2021 Mar 31. e1368
    Statins and immunotherapy: Togetherness makes strength The potential effect of statins on immunotherapy for NSCLC.
    Rossi A, Filetti M, Taurelli Salimbeni B, Piras M, Rizzo F, Giusti R, Marchetti P.
      BACKGROUND: Recent researches suggested that statins, beside their role in inhibiting endogenous cholesterol synthesis and in cardiovascular prevention, could influence several processes in cancer biology. In fact, a recent meta-analysis demonstrated that statins could positively influence OS in lung cancer patients.AIM: There is a lack of large cohort studies that could support a potential antineoplastic role of statins in clinical practice. We collected data from 162 patients treated with immunotherapy for Nonsmall Cell Lung Cancer (NSCLC) in first- and second-line setting to investigate the impact of these drugs on survival parameters.
    METHODS AND RESULTS: In our observational study, we enrolled 162 patients who received immunotherapy for lung cancer between October 2015 and April 2020. We used descriptive statistics to analyze patients' baseline features. Tumor response was evaluated using RECIST version 1.1 guidelines. Uni and multivariate analysis were conducted to investigate the relationship between statin use and response to immunotherapy, using the χ2 -test. We used Kaplan-Meier curves to estimate OS and PFS in statin and nonstatin users. We included 122 patients in the final analysis. Median PFS was 17.57 months in the statin group and 9.57 months in the nonstatin group, with a P = <.001. Moreover, median OS was superior in the statin-users group, with a statistically significant difference (19.94 vs 10.94 months, P = <.001).
    CONCLUSION: Although in our study, statin use positively correlates with PFS and OS in lung cancer patient treated with immunotherapy, these results require a further validation with randomized clinical trials.
    Keywords:  NSCLC; immunotherapy; lung cancer; statins; survival
    DOI:  https://doi.org/10.1002/cnr2.1368
  4. Cancers (Basel). 2021 Mar 05. pii: 1112. [Epub ahead of print]13(5):
    Metabolic Health Together with a Lipid Genetic Risk Score Predicts Survival of Small Cell Lung Cancer Patients.
    Fernández LP, Merino M, Colmenarejo G, Moreno Rubio J, González Pessolani T, Reglero G, Casado E, Sereno M, Ramírez de Molina A.
      Small cell lung cancer (SCLC) prognosis is the poorest of all types of lung cancer. Its clinical management remains heterogeneous and therefore, the capability to predict survival would be of great clinical value. Metabolic health (MH) status and lipid metabolism are two relevant factors in cancer prevention and prognosis. Nevertheless, their contributions in SCLC outcome have not yet been analyzed. We analyzed MH status and a transcriptomic panel of lipid metabolism genes in SCLC patients, and we developed a predictive genetic risk score (GRS). MH and two lipid metabolism genes, racemase and perilipin 1, are biomarkers of SCLC survival (HR = 1.99 (CI95%: 1.11-3.61) p = 0.02, HR = 0.36 (CI95%: 0.19-0.67), p = 0.03 and HR = 0.21 (CI95%: 0.09-0.47), respectively). Importantly, a lipid GRS of these genes predict better survival (c-index = 0.691). Finally, in a Cox multivariate regression model, MH, lipid GRS and smoking history are the main predictors of SCLC survival (c-index = 0.702). Our results indicate that the control of MH, lipid gene expression and environmental factors associated with lifestyle is crucial for increased SCLC survival. Here, we propose for the first time, a metabolic precision approach for SCLC patients.
    Keywords:  gene expression profile; high stage tumors; lipid metabolism; metabolic health; prognosis; small cell lung cancer
    DOI:  https://doi.org/10.3390/cancers13051112
  5. Int J Mol Sci. 2021 Mar 25. pii: 3378. [Epub ahead of print]22(7):
    Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia.
    Martín-Bernabé A, Tarragó-Celada J, Cunin V, Michelland S, Cortés R, Poignant J, Boyault C, Rachidi W, Bourgoin-Voillard S, Cascante M, Seve M.
      Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.
    Keywords:  NSCLC; cancer metabolism; hypoxia; lysine deacetylase inhibitors
    DOI:  https://doi.org/10.3390/ijms22073378
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