Retinoic acid induces a metabolic switch in SH‐SY5Y cells from glycolysis to oxidative phosphorylation

Abstract

Retinoic acid (RA) is used in differentiation therapy to treat a variety of cancers including neuroblastoma. The basis for its therapeutic efficacy is unknown, however, mitochondria (MT) have been implicated as key effectors in RA‐mediated differentiation process. Here we use the SH‐SY5Y human neuroblastoma cell line as a model to examine the contribution of MT to the physiological effects of RA treatment. We find that RA induces a dramatic increase in the energy metabolism of SH‐SY5Y cells, and shifts the dependence on energy production from glycolysis to oxidative phosphorylation. RA treatment does not increase the number of MT or cause measurable changes in the composition of the electron transport chain. Rather, RA treatment elevates the production of intracellular pyruvate as fuel for mitochondrial consumption, and significantly enhances the mitochondrial respiratory capacity. We propose a competition model for the therapeutic effects of RA. Specifically, the high metabolic rate in differentiated cells limits the availability of metabolic nutrients for use by the undifferentiated cells and suppresses their growth. Thus, RA treatment provides a selective advantage for the differentiated state.