Overexpression of catalase or Bcl-2 alters glucose and energy metabolism concomitant with dexamethasone resistance

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27 Scopus citations

Abstract

Glucocorticoids induce apoptosis in lymphocytes by causing the release of cytochrome c into the cytosol; however, the events in the signaling phase between translocation of the steroid-receptor complex to the nucleus and the release of cytochrome c have not been elucidated. Previously, we found that, in response to steroid treatment, WEHI7.2 mouse thymic lymphoma cells overexpressing catalase (CAT38) show delayed apoptosis (delayed cytochrome c release) compared to the parental cells, while Bcl-2 overexpressing cells (Hb12) are protected from steroid-induced apoptosis. In lymphocytes, glucocorticoid treatment decreases glucose uptake. Both glucose deprivation and the attendant ATP drop are known inducers of apoptosis. Therefore, we used 31P and 1H NMR spectroscopy to compare metabolic profiles of WEHI7.2, CAT38 and Hb12 cells in the presence and absence of dexamethasone to determine: (1) whether glucocorticoid effects on glucose metabolism contribute to the mechanism of steroid-induced apoptosis; and (2) whether catalase or Bcl-2 overexpression altered metabolism thereby providing a mechanism of steroid resistance. Loss of mitochondrial hexokinase activity was correlated to the induction of apoptosis in WEHI7.2 and CAT38 cells. CAT38 and Hb12 cells have an altered basal metabolism which includes increases in hexokinase activity, lactate production when subcultured into new medium, use of mitochondria for ATP production and potentially increased glutaminolysis. These data suggest that: (1) glucocorticoid effects on glucose metabolism may contribute to the mechanism of steroid-induced lymphocyte apoptosis; and (2) the altered metabolism seen in catalase and Bcl-2 overexpressing cells may contribute to both the steroid resistance and increased tumorigenicity of these variants.

Original languageEnglish (US)
Pages (from-to)57-72
Number of pages16
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1693
Issue number1
DOIs
StatePublished - Jul 23 2004

Keywords

  • Apoptosis
  • CAT38
  • CCCP
  • EtOH
  • Gro-3-P
  • Hexokinase
  • Lymphocyte
  • NMR
  • Steroid
  • WEHI7.2 cells expressing 1.4-fold parental cell catalase
  • ala
  • alanine
  • asp
  • aspartate
  • carbonyl cyanide m-chlorophenylhydrazine
  • ethanol
  • gln
  • glu
  • glutamate
  • glutamine
  • glycerol 3-phosphate

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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