Micromanaging aerobic respiration and glycolysis in cancer cells

Abstract

Background: Cancer cells possess a common metabolic phenotype, rewiring their metabolic pathways from mitochondrial oxidative phosphorylation to aerobic glycolysis and anabolic circuits, to support the energetic and biosynthetic requirements of continuous proliferation and migration. While, over the past decade, molecular and cellular studies have clearly highlighted the association of oncogenes and tumor suppressors with cancer-associated glycolysis, more recent attention has focused on the role of microRNAs (miRNAs) in mediating this metabolic shift. Accumulating studies have connected aberrant expression of miRNAs with direct and indirect regulation of aerobic glycolysis and associated pathways.

Scope of review: This review discusses the underlying mechanisms of metabolic reprogramming in cancer cells and provides arguments that the earlier paradigm of cancer glycolysis needs to be updated to a broader concept, which involves interconnecting biological pathways that include miRNA-mediated regulation of metabolism. For these reasons and in light of recent knowledge, we illustrate the relationships between metabolic pathways in cancer cells. We further summarize our current understanding of the interplay between miRNAs and these metabolic pathways. This review aims to highlight important metabolism-associated molecular components in the hunt for selective preventive and therapeutic treatments.

Major conclusions: Metabolism in cancer cells is influenced by driver mutations but is also regulated by posttranscriptional gene silencing. Understanding the nuanced regulation of gene expression in these cells and distinguishing rapid cellular responses from chronic adaptive mechanisms provides a basis for rational drug design and novel therapeutic strategies.

Keywords: Aerobic glycolysis; Cancer; Metabolism; Warburg effect; microRNA.

Figure 1

miRNAs targeting glycolytic and mitochondrial enzymes.

Figure 2

Interconnections between the drivers and suppressors of glycolysis, and the role of miRNAs in these networks. Protein–protein interactions identified using String V10.0. Solid blue lines indicate protein activation while solid red lines indicate protein inhibition. Dotted blue and red lines represent transcription factor-mediated activation or inhibition of the miRNAs, respectively. miRNAs in pink boxes repress gene expression, while those in orange and blue boxes indicate miRNAs that are inhibited or activated by the transcription factors, respectively. Specific miRNAs present in both the pink boxes and either the orange or blue boxes, may represent feedback loops in particular cellular contexts.