Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Leithner, K.
The role of phosphoenolpyruvate carboxykinase
in lung cancer
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 75
[OPEN ACCESS]
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Hrzenjak Andelko
- Olschewski Horst
- Altmetrics:
- Abstract:
- Cancer cells are re-programmed to utilize glycolysis at high rates, which provides building blocks for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis, the generation of glucose from small carbon substrates, is the reverse of glycolysis in many aspects, but differs in the requirement for phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1,6-biphosphatase. PEPCK, which generates phosphenolpyruvate (PEP) from oxaloacetate, has been shown to provide metabolites for cell growth. Still, the role of PEPCK in cancer is unknown. In the present work it is shown that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low glucose. PEPCK activity was elevated threefold in lung cancer samples over normal lungs and contributed to the PEP pool under low glucose, as shown by stable isotope analyses using 13C3-lactate. PEPCK inhibition using 3-mercaptopicolinate or PCK2 siRNA significantly enhanced glucose depletion-induced apoptosis in lung cancer cells carrying an inactivating LKB1 (lymphoma kinase B1) mutation. Furthermore, 3-mercaptopicolinate significantly reduced the growth of multicellular spheroids. In conclusion, lung cancer cells utilize at least some steps of gluconeogenesis and by this way adapt to glucose deprivation.