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

FEBS Letters

Papas, Klearchos K²  Shapiro, Michael²  Nalin, Carlo M¹  Gounarides, John S²  Roos, Eric S²  Sun, Lei¹ 

[1] Oncology Research, Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, Summit, NJ 07901, USA;Core Technologies/Analytics and Bio-NMR US, Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, Summit, NJ 07901, USA

关键词: Bcl-2;    Apoptosis;    Rat1-Myc;    Staurosporine;    Lactate production;    FBS;    fetal bovine serum;    DMEM;    Dulbecco's modified Eagle's medium;    GCR;    glucose consumption rate;    LPR;    lactate production rate;   

DOI  :  10.1016/S0014-5793(99)00240-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown