Abstract
The glycolytic enzyme pyruvate kinase (PK) is required for cancer development, and has been implicated in the metabolic transition from oxidative to fermentative metabolism, the Warburg effect. However, the global metabolic response that follows changes in PK activity is not yet fully understood. Using shotgun proteomics, we identified 31 yeast proteins that were regulated in a PK-dependent manner. Selective reaction monitoring confirmed that their expression was dependent on PK isoform, level and activity. Most of the PK targets were amino acid metabolizing enzymes or factors of protein translation, indicating that PK plays a global regulatory role in biosynthethic amino acid metabolism. Indeed, we found strongly altered amino acid profiles when PK levels were changed. Low PK levels increased the cellular glutamine and glutamate concentrations, but decreased the levels of seven amino acids including serine and histidine. To test for evolutionary conservation of this PK function, we quantified orthologues of the identified PK targets in thyroid follicular adenoma, a tumor characterized by high PK levels and low respiratory activity. Aminopeptidase AAP-1 and serine hydroxymethyltransferase SHMT1 both showed PKM2- concentration dependence, and were upregulated in the tumor. Thus, PK expression levels and activity were important for maintaining cellular amino acid homeostasis. Mediating between energy production, ROS clearance and amino acid biosynthesis, PK thus plays a central regulatory role in the metabolism of proliferating cells.
Highlights
Cancer cell growth is characterized by reconfiguration of cellular metabolism
Changes in pyruvate kinase (PK) isoform and expression levels are observed when cells switch from fermentation to oxidative metabolism [17, 21], indicting that PK plays an evolutionary conserved role in the underlining metabolic reconfiguration
Interest in PKM2 had increased markedly after it had been suggested that PKM2 expression in adults could be specific to cancer cells, and that a PKM1 to PKM2 isoform switch might be responsible for increased fermentative metabolism (Warburg effect) of cancer cells [34, 35]
Summary
Cancer cell growth is characterized by reconfiguration of cellular metabolism. Different routes of intermediary and biosynthetic metabolism, including nucleic acid synthesis, amino acid biosynthesis, and energy production are reconfigured [1,2,3,4]. ROS originate from biochemical reactions, i.e. the degradation of fatty acids, and leakage from complex I and III of the respiratory chain [11, 12] Clearing of these reactive molecules prevents oxidative stress, and is conducted by large machinery which involves central carbon metabolism as essential metabolic component. Fluxes of glycolysis and the adjacent pentose phosphate pathway (PPP) are adjusted when cells encounter an oxidative environment [13]. This metabolic reconfiguration fuels the antioxidative machinery with its main redox cofactor NADPH, required by the glutathione, peroxiredoxin and thioredoxin systems [14, 15], and is involved in regulating gene expression during oxidative conditions [16]
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