Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities

Abstract

Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Due to differential regulation of enzymatic activities, PKM2 but not PKM1 has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC over-expression in murine livers did not affect c-MYC induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC-induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process.

Identifying strategies to target the metabolic flexibility of tumours

“…1b). These results suggested that glucose catabolism through glycolysis and catabolism of both glucose and glutamine through the Krebs cycle are increased on MYC-induced liver tumours in comparison with normal tissue counterparts consistent with our previously published results 10,12 .…”

“…2c). To induce MYCdriven tumours in this case we used hydrodinamics-based transfection of a MYC-encoding plasmid 12,27 . Since ectopic expression of Cre recombinase has been previously shown to exacerbate MYC-induced apoptosis and reduce the efficiency of MYC-induced tumourigenesis 28 , we also combined the ectopic expression of MYC with the expression of MCL1, another gene frequently overexpressed in human liver tumours (Extended Data Fig.…”

“…Using a genetically engineered mouse model of liver cancer 9 we and others have demonstrated that MYC-induced liver tumours have increased catabolism of both glucose and glutamine in comparison with the normal liver 10,11 . These metabolic changes are associated with a repression of some liver-specific enzymes as well as the expression of enzyme isoforms that are not expressed in the normal liver [10][11][12] , including glutaminase 1 (GLS1) that catalyses the first step of glutamine catabolism, and the HK2 isoform of the first enzyme of glycolysis, hexokinase. Since both glucose and glutamine fuel pathways that are vital for proliferation and survival of cells, including the Krebs cycle, or serine, nucleotide, and lipid biosynthesis 4,[13][14][15][16] , several enzymes controlling these pathways have been considered as attractive therapeutic targets 4,10,[17][18][19][20][21] .…”

Crosstalk of mTOR/PKM2 and STAT3/c‐Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer

“…c‐Myc is an important member of the Myc gene family and is involved in the development of various tumors. It plays an important role in tumor energy metabolism, regulates glycolysis, and promotes the Warburg effect in tumor . Pyruvate kinase is a key enzyme in the last step of glycolysis that transfers a phosphate group from phosphoenolpyruvate to ADP, resulting in the formation of pyruvate and an ATP molecule .…”

Discovery of functional alternatively splicedPKMtranscripts in human cancers

“…Previous studies reported that the ratio between PKM1 and PKM2 isoforms plays a key role in cancer progression 34-38 . In our study, we found PKM1 is not stronglyassociated with the survival of cancer patients as it has been reported 18 .…”