Bcl-2 or Bcl-xL Overexpression Stimulates Lactic Fermentation without Affecting Whole Cell Respiration

Abstract

It is now well established that shifts in energy metabolism are associated with cancer development and progression. The most studied of these phenomena is the Warburg effect, which corresponds to an increase of anaerobic glycolysis vs mitochondrial oxidative phosphorylation to produce energy for cellular processes. However, the mechanisms related to these metabolic switches are still a matter of debate. Bcl-2 family proteins contain both pro- (e.g. Bax), and anti-apoptotic (e.g. Bcl-2 and Bcl-xL) members which are respectively encoded by tumor suppressors and proto-oncogenes. Up-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL have been associated with Non-Hodgkin's lymphoma; and certain studies indicate that Bcl-2 family proteins play a role in the regulation of energy metabolism. However, the molecular players involved in this regulation are still to be defined. We recently observed that Bcl-2 or Bcl-xL (Bcl-2/xL) overexpression led to a significant increase of lactate production rates in a mouse pro-lymphocyte B cell line. However, both lactate production and glucose consumption fluxes are stimulated by Bcl-2/xL overexpression. Also, basal, uncoupled and non-coupled whole cell respiration remain similar in the 3 cell lines. Taken together, these results suggest that the fermentative component, but not the oxidative component, of carbohydrate metabolism is stimulated in these genetic contexts. This phenomenon is associated with an increase of glycolytic/fermentative (LDH and GAPDH enzyme activity) and mitochondrial (Citrate synthase activity) markers; but only when Bcl-xL (and not Bcl-2) is overexpressed. These data suggest that Bcl-2 and Bcl-xL expression levels may play an active role in the stimulation of lactic fermentation commonly observed in blood cancer cells; and that Bcl-2 and Bcl-xL-mediated stimulation of lactate production are the results of different molecular mechanisms.