bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2018‒12‒09
two papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Co-occurring KRAS mutation/LKB1 loss in non-small cell lung cancer cells results in enhanced metabolic activity susceptible to caloric restriction: an in vitro integrated multilevel approach.
  2. LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma.
  1. J Exp Clin Cancer Res. 2018 Dec 04. 37(1): 302
    Co-occurring KRAS mutation/LKB1 loss in non-small cell lung cancer cells results in enhanced metabolic activity susceptible to caloric restriction: an in vitro integrated multilevel approach.
    Caiola E, Falcetta F, Giordano S, Marabese M, Garassino MC, Broggini M, Pastorelli R, Brunelli L.
      BACKGROUND: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, with multiple different oncogenic mutations. Approximately 25-30% of NSCLC patients present KRAS mutations, which confer poor prognosis and high risk of tumor recurrence. About half of NSCLCs with activating KRAS lesions also have deletions or inactivating mutations in the serine/threonine kinase 11 (LKB1) gene. Loss of LKB1 on a KRAS-mutant background may represent a significant source of heterogeneity contributing to poor response to therapy.METHODS: Here, we employed an integrated multilevel proteomics, metabolomics and functional in-vitro approach in NSCLC H1299 isogenic cells to define their metabolic state associated with the presence of different genetic background. Protein levels were obtained by label free and single reaction monitoring (SRM)-based proteomics. The metabolic state was studied coupling targeted and untargeted mass spectrometry (MS) strategy. In vitro metabolic dependencies were evaluated using 2-deoxy glucose (2-DG) treatment or glucose/glutamine nutrient limitation.
    RESULTS: Here we demonstrate that co-occurring KRAS mutation/LKB1 loss in NSCLC cells allowed efficient exploitation of glycolysis and oxidative phosphorylation, when compared to cells with each single oncologic genotype. The enhanced metabolic activity rendered the viability of cells with both genetic lesions susceptible towards nutrient limitation.
    CONCLUSIONS: Co-occurrence of KRAS mutation and LKB1 loss in NSCLC cells induced an enhanced metabolic activity mirrored by a growth rate vulnerability under limited nutrient conditions relative to cells with the single oncogenetic lesions. Our results hint at the possibility that energy stress induced by calorie restriction regimens may sensitize NSCLCs with these co-occurring lesions to cytotoxic chemotherapy.
    Keywords:  Caloric restriction; Co-occurring genetic lesions; KRASG12C mutation; LKB1 loss; Metabolomics; NSCLC
    DOI:  https://doi.org/10.1186/s13046-018-0954-5
  2. Biosci Rep. 2018 Dec 03. pii: BSR20181476. [Epub ahead of print]
    LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma.
    Hou XM, Yuan SQ, Zhao D, Liu XJ, Wu XA.
      Lactate dehydrogenase A (LDH-A) is a key enzyme during glycolysis, which increases the synthesis of related proteins and has elevated activity in cancer cells. The role of LDH-A in lung adenocarcinoma (LUAD) progression was investigated in this study. Expression levels of LDH-A were assessed in LUAD samples，and the relationship between LDH-A expression status and the prognosis of LUAD patients was confirmed. The effect of LDH-A on proliferation, invasion, migration, and colony formation of cancer cells was assessed. We further determined the role of LDH-A in tumor growth in   vivo  by using xenograft LUAD tumor models. The potential mechanism of LDH-A promotion in LUAD progression was explored. LDH-A showed an abnormally high expression in LUAD, which is closely associated with poor prognosis in patients with LUAD. In  in vitro  experiments, silencing LDH-A expression in LUAD cells could effectively inhibit proliferation, invasion, migration, and colony formation of cancer cells. In in   vivo  experiments, tumor growth was markedly inhibited by LDH-A silencing in a xenograft model of LUAD. Notably, LDH-A could also promote tumor progression by regulating epithelial-mesenchymal transition (EMT)-related molecules. LDH-A can promote the malignant biological behaviors of LUAD cells, and thus can be a potential target for LUAD treatment.
    Keywords:  EMT; LDH-A; LUAD; Prognosis; Tumor progression
    DOI:  https://doi.org/10.1042/BSR20181476
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