One way that cancer cells differ from normal cells is in the way that they process nutrients; that is, they divert a greater fraction of the intermediates of glucose metabolism into the anabolic processes of nucleotide, protein and lipid synthesis rather than oxidative phosphorylation. As a consequence, tumor cells typically require a much higher rate of glucose consumption to balance their altered metabolic demands. Indeed, microarray studies have shown that glycolytic genes comprise one of the most upregulated gene sets in cancer. Among the genes involved in glucose metabolism upregulated in cancer is pyruvate kinase (PK), the enzyme that catalyzes the transfer of a phosphate from phosphoenolpyruvate (PEP) to ADP to yield pyruvate and ATP.

Glucose Metabolism in Differentiated Versus Proliferative Tissue. In aerobic environments (with oxygen), differentiated tissues use PKM1 to drive pyruvate into the mitochondria for ATP generation. In anaerobic environments (without oxygen), the mitochondria cannot be utilized and pyruvate is converted into lactate. Rapidly proliferating tissue/tumors use PKM2 to divert glycolytic metabolites into anabolic processes and lactate, both in the presence and absence of oxygen (+/– oxygen). Figure adapted from Vander Heiden MG, Cantley LC, et al. Science, 2009.

PK is encoded by the Pyk M gene, which produces two alternatively spliced mRNAs. The first encodes the M1 isozyme (PKM1) which is found in many adult, differentiated tissues. In fetal tissue, alternative splicing results in M2 isozyme (PKM2) expression, the characteristic form observed in proliferating cells. Early genetic observations recognized that the adult PK isozyme is replaced by PKM2 in tumor cells. This switch from PKM1 to PKM2 allows cancer cells to control how glucose is processed (see Figure inset). Indeed, it is now broadly appreciated that PKM2 is expressed at high levels in a wide spectrum of tumors, a fact that has led to its use as a cancer biomarker. Furthermore, members of the Cantley lab have recently demonstrated that the altered metabolic state of cancer cells can be reversed, and tumorigenicity can be stunted in cancer cell lines when PKM1 is expressed simultaneous to the silencing of PKM2.

The reaction catalyzed by PK is the final step in glycolysis; it is also irreversible and thus rate-limiting. Based on its position at this critical point in glucose metabolism and its role in tumorigenicity, it may act in some way to coordinate metabolic and transcriptional activity. The focus of Costas' research in the Cantley lab is aimed at exploring under appreciated transcriptional control mechanisms that are regulated by cellular nutrient levels. Specifically, he is studying the nuclear role of PKM2 in pancreatic cancer through a collaboration with the Hanahan lab at the EPFL. Ultimately, this line of investigation will provide insight into our understanding of the altered metabolic state of, and aims to identify new metabolic drug targets in, pancreatic adenocarcinoma – a disease for which targeted therapies are in desperate need.