Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Smolle, E; Leko, P; Stacher-Priehse, E; Brcic, L; El-Heliebi, A; Hofmann, L; Quehenberger, F; Hrzenjak, A; Popper, HH; Olschewski, H; Leithner, K.
Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.
Mol Oncol. 2020; 14(11):2853-2867
Doi: 10.1002/1878-0261.12780
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Web of Science
PubMed
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- Leading authors Med Uni Graz
- Leithner Katharina
- Taucher Elisabeth
- Co-authors Med Uni Graz
- Bonstingl Lilli
- Brcic Luka
- El-Heliebi Amin
- Hrzenjak Andelko
- Leko Petra
- Olschewski Horst
- Popper Helmuth
- Quehenberger Franz
- Stacher-Priehse Elvira
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- Abstract:
- Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.
- Find related publications in this database (using NLM MeSH Indexing)
- Carcinoma, Non-Small-Cell Lung - diagnosis, metabolism
- Cell Line, Tumor - administration & dosage
- Female - administration & dosage
- Gluconeogenesis - administration & dosage
- Glucose Transporter Type 1 - analysis, metabolism
- Glycolysis - administration & dosage
- Humans - administration & dosage
- Intracellular Signaling Peptides and Proteins - analysis, metabolism
- Lung Neoplasms - diagnosis, metabolism
- Male - administration & dosage
- Phosphoenolpyruvate Carboxykinase (ATP) - analysis, metabolism
- Phosphoenolpyruvate Carboxykinase (GTP) - analysis, metabolism
- Prognosis - administration & dosage
- Find related publications in this database (Keywords)
- gluconeogenesis
- GLUT1
- glycolysis
- lung cancer
- PCK2