bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2019‒09‒22
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cell Metab. 2019 Aug 29. pii: S1550-4131(19)30443-7. [Epub ahead of print]
    Sun RC, Dukhande VV, Zhou Z, Young LEA, Emanuelle S, Brainson CF, Gentry MS.
      Nuclear glycogen was first documented in the early 1940s, but its role in cellular physiology remained elusive. In this study, we utilized pure nuclei preparations and stable isotope tracers to define the origin and metabolic fate of nuclear glycogen. Herein, we describe a key function for nuclear glycogen in epigenetic regulation through compartmentalized pyruvate production and histone acetylation. This pathway is altered in human non-small cell lung cancers, as surgical specimens accumulate glycogen in the nucleus. We demonstrate that the decreased abundance of malin, an E3 ubiquitin ligase, impaired nuclear glycogenolysis by preventing the nuclear translocation of glycogen phosphorylase and causing nuclear glycogen accumulation. Re-introduction of malin in lung cancer cells restored nuclear glycogenolysis, increased histone acetylation, and decreased growth of cancer cells transplanted into mice. This study uncovers a previously unknown role for glycogen metabolism in the nucleus and elucidates another mechanism by which cellular metabolites control epigenetic regulation.
    Keywords:  E3 ubiquitin ligase; EPM2B; Lafora disease; NHLRC1; glycogen; glycogen phosphorylase; histone acetylation; malin; non-small cell lung cancer; nuclear metabolism
  2. Int J Mol Med. 2019 Sep;44(3): 1026-1038
    Wang J, Zhang Y, Liu X, Wang J, Li B, Liu Y, Wang J.
      Lung cancer is one of the leading causes of cancer‑associated mortality in China and globally. Gemcitabine (GEM), as a first‑line therapeutic drug, has been used to treat lung cancer, but GEM resistance poses a major limitation on the efficacy of GEM chemotherapy. Alantolactone (ALT), a sesquiterpene lactone compound isolated from Inula helenium, has been identified to exert anticancer activity in various types of cancer, including breast, pancreatic, lung squamous and colorectal cancer. However, the underlying mechanisms of the anticancer activity of ALT in lung cancer remain to be fully elucidated. The present study aimed to determine whether ALT enhances the anticancer efficacy of GEM in lung cancer cells and investigated the underlying mechanisms. The cell viability was assessed with a Cell Counting Kit‑8 assay. The cell cycle, apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression of cell cycle‑associated and apoptosis‑associated proteins were determined by western blot analysis. The results demonstrated that ALT inhibited cell growth and induced S‑phase arrest and cell apoptosis in A549 and NCI‑H520 cells. Furthermore, ALT increased the level of ROS, inhibited the Akt/glycogen synthase kinase (GSK)3β pathway and induced endoplasmic reticulum (ER) stress in A549 and NCI‑H520 cells. Additionally, ALT treatment sensitized lung cancer cells to GEM. Analysis of the molecular mechanisms further revealed that ALT enhanced the anticancer effects of GEM via ROS‑mediated activation of the Akt/GSK3β and ER stress pathways. In conclusion, combined treatment with ALT and GEM may have potential as a clinical strategy for lung cancer treatment.
  3. J Cell Physiol. 2019 Sep 20.
    Gai C, Yu M, Li Z, Wang Y, Ding D, Zheng J, Lv S, Zhang W, Li W.
      Growing evidence confirms that ferroptosis plays an important role in tumor growth inhibition. However, some non-small-cell lung cancer (NSCLC) cell lines are less sensitive to erastin-induced ferroptotic cell death. Elucidating the mechanism of resistance of cancer cells to erastin-induced ferroptosis and increasing the sensitivity of cancer cells to erastin need to be addressed. In our experiment, erastin and acetaminophen (APAP) cotreatment inhibited NSCLC cell viability and promoted ferroptosis and apoptosis, accompanied with attenuation of glutathione and ectopic increases in lipid peroxides. Erastin and APAP promoted NSCLC cell death by regulating nucleus translocation of nuclear factor erythroid 2-related factor 2 (Nrf2); and the ferroptosis induced by erastin and APAP was abrogated by bardoxolone methyl (BM) with less generation of reactive oxygen species and malondialdehyde. As a downstream gene of Nrf2, heme oxygenase-1 expression decreased significantly with the cotreatment of erastin and APAP, which could be rescued by BM. In vivo experiment showed that the combination of erastin and APAP had a synergic therapeutic effect on xenograft of lung cancer. In short, the present study develops a new effective treatment for NSCLC by synergizing erastin and APAP to induce ferroptosis.
    Keywords:  Nrf2; acetaminophen; erastin; ferroptosis; non-small-cell lung cancer
  4. Theranostics. 2019 ;9(21): 6157-6174
    Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu CS, Chen L, Chin TM, Tenen DG.
      Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.
    Keywords:  Cav1; EGFR-TKI resistance; GLUT3; Statin; glucose uptake; non-small cell lung cancer