Change in lactate production in Myc-transformed cells precedes apoptosis and can be inhibited by Bcl-2 overexpression

Klearchos K Papas, Lei Sun, Eric S. Roos, John S. Gounarides, Michael Shapiro, Carlo M. Nalin

Research output: Contribution to journalArticle

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Abstract

As a result of Myc-dependent transcription of the LDH-A gene, Myc-transformed cells (Rat1-Myc) exhibit increased lactate production rates (LPR) even under aerobic conditions (the Warburg effect). Recently, the increased susceptibility to stress-induced apoptosis associated with Myc transfection has been linked to the overexpression of the LDH-A gene. In this report we demonstrate that the overexpression of the anti-apoptotic protein Bcl-2 in Rat1-Myc cells (Rat1-Myc-Bcl-2) reduces the molar ratio of lactate production to glucose consumption (Y(L/G)). The Bcl-2 induced reduction in Y(L/G) may be associated with reduced expression of the LDH-A gene, or a decrease in LDH-A activity. Stimulation of apoptosis by staurosporine, a protein kinase C inhibitor, reduces the LPR in Rat1-Myc cells in a dose-dependent manner. The staurosporine effect on the LPR is rapid and precedes the execution phase of apoptosis as defined by caspase activation and PARP cleavage. This effect on LPR is completely blocked by Bcl-2 overexpression. Serum starvation alone does not affect the LPR of Rat1-Myc or Rat1-Myc-Bcl-2 cells; however, the effect of staurosporine on the LPR of Rat1-Myc cells is potentiated by serum starvation. These data demonstrate that Bcl-2 overexpression reduces the Y(L/G) in Rat1-Myc cells, perhaps via a reduction in the activity or expression of the LDH-A gene, and this reduction may desensitize cells to some pro-apoptotic stimuli. The reduction in LPR in response to staurosporine may be an early step in the induction of apoptosis in Rat1-Myc cells. By abolishing the reduction in LPR, Bcl-2 may protect Rat1-Myc cells from staurosporine-induced apoptosis. Moreover, the lack of effect by serum starvation on the LPR supports a model in which serum starvation induces apoptosis through a pathway distinct from that of the staurosporine and glucose-dependent apoptotic pathway(s) in Myc-transformed cells. Copyright (C) 1999 Federation of European Biochemical Societies.

Original languageEnglish (US)
Pages (from-to)338-342
Number of pages5
JournalFEBS Letters
Volume446
Issue number2-3
DOIs
StatePublished - Mar 12 1999
Externally publishedYes

Fingerprint

Lactic Acid
Staurosporine
Apoptosis
Starvation
Genes
Serum
Glucose
Apoptosis Regulatory Proteins
myc Genes
Protein C Inhibitor
Transcription
Protein Kinase Inhibitors
Caspases
Protein Kinase C
Transfection
Chemical activation
lactate dehydrogenase 5

Keywords

  • Apoptosis
  • Bcl-2
  • Lactate production
  • Rat1-Myc
  • Staurosporine

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Change in lactate production in Myc-transformed cells precedes apoptosis and can be inhibited by Bcl-2 overexpression. / Papas, Klearchos K; Sun, Lei; Roos, Eric S.; Gounarides, John S.; Shapiro, Michael; Nalin, Carlo M.

In: FEBS Letters, Vol. 446, No. 2-3, 12.03.1999, p. 338-342.

Research output: Contribution to journalArticle

Papas, Klearchos K ; Sun, Lei ; Roos, Eric S. ; Gounarides, John S. ; Shapiro, Michael ; Nalin, Carlo M. / Change in lactate production in Myc-transformed cells precedes apoptosis and can be inhibited by Bcl-2 overexpression. In: FEBS Letters. 1999 ; Vol. 446, No. 2-3. pp. 338-342.
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AU - Nalin, Carlo M.

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N2 - As a result of Myc-dependent transcription of the LDH-A gene, Myc-transformed cells (Rat1-Myc) exhibit increased lactate production rates (LPR) even under aerobic conditions (the Warburg effect). Recently, the increased susceptibility to stress-induced apoptosis associated with Myc transfection has been linked to the overexpression of the LDH-A gene. In this report we demonstrate that the overexpression of the anti-apoptotic protein Bcl-2 in Rat1-Myc cells (Rat1-Myc-Bcl-2) reduces the molar ratio of lactate production to glucose consumption (Y(L/G)). The Bcl-2 induced reduction in Y(L/G) may be associated with reduced expression of the LDH-A gene, or a decrease in LDH-A activity. Stimulation of apoptosis by staurosporine, a protein kinase C inhibitor, reduces the LPR in Rat1-Myc cells in a dose-dependent manner. The staurosporine effect on the LPR is rapid and precedes the execution phase of apoptosis as defined by caspase activation and PARP cleavage. This effect on LPR is completely blocked by Bcl-2 overexpression. Serum starvation alone does not affect the LPR of Rat1-Myc or Rat1-Myc-Bcl-2 cells; however, the effect of staurosporine on the LPR of Rat1-Myc cells is potentiated by serum starvation. These data demonstrate that Bcl-2 overexpression reduces the Y(L/G) in Rat1-Myc cells, perhaps via a reduction in the activity or expression of the LDH-A gene, and this reduction may desensitize cells to some pro-apoptotic stimuli. The reduction in LPR in response to staurosporine may be an early step in the induction of apoptosis in Rat1-Myc cells. By abolishing the reduction in LPR, Bcl-2 may protect Rat1-Myc cells from staurosporine-induced apoptosis. Moreover, the lack of effect by serum starvation on the LPR supports a model in which serum starvation induces apoptosis through a pathway distinct from that of the staurosporine and glucose-dependent apoptotic pathway(s) in Myc-transformed cells. Copyright (C) 1999 Federation of European Biochemical Societies.

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