Bcl-2 or Bcl-xL Overexpresssion Affects Both Lactic Fermentation and Mitochondrial Metabolism in Growing Pro-Lymphocytes

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 metabolic phenotypes associated directly with an overexpression of Bcl-2 or Bcl-xL (Bcl-2/xL) remain to be defined at the whole cell level. We recently applied a 1H- and 13C-NMR-based approach on growing Bcl-2/xL-overexpressing pro-lymphocyte B cell lines to determine their respective metabolic trends. The comparison of 1H-NMR spectra obtained from whole cell metabolites extractions indicate that significant metabolic changes are induced by Bcl-2/xL-overexpression; more particularly at the level of the intracellular fumarate pool. Also, both lactate production and glucose consumption fluxes are stimulated by Bcl-2/xL overexpression. 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 transduction mechanisms.