Bcl-2 Overexpression Stimulates Glycolysis and Lactic Fermentation in a Bax-Dependent Fashion

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) members which are respectively encoded by tumor suppressors and proto-oncogenes. Up-regulation of the anti-apoptotic proteins Bcl-2 has been associated with Non-Hodgkin's lymphoma; and certain studies indicate that Bcl-2 plays 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 overexpression led a significant increase of both glucose consumption and lactate production rates in a mouse pro-lymphocyte B cell line. This phenomenon was associated with a stimulation of the lactate dehydrogenase (LDH) enzyme specific activity; and a Bcl-2-mediated increase of the expression of the LDH-A subunit. Also, this phenotype was strongly attenuated if a Bcl-2 mutant of interaction with Bax (Bcl-2-G145E) was overexpressed instead of native Bcl-2. These data suggest that Bcl-2 expression levels may play an active role in the stimulation of lactic fermentation commonly observed in blood cancer cells; and that this effect may be dependent to the ability of Bcl-2 to physically interact with Bax.