Researchers from Shanghai Jiaotong University confirmed in a new study that PIM2 can directly phosphorylate PKM2 in cancer cells to promote glycolysis. This research was published online in the October 18 issue of "Journal of Biochemistry" (JBC).
Professor Gang Huang of Shanghai Jiaotong University is the corresponding author of this paper. The main research directions include tumor metabolic mechanism and molecular imaging evaluation, tumor efficacy evaluation and target role research, absolute quantitative research of molecular imaging and image fusion.
Tumor cells will only proliferate when sufficient energy and components are obtained. Compared with normal tissues, the glucose utilization of most tumors is significantly increased, which is called the Warburg effect. Due to changes in glycolytic enzymes, even in the presence of oxygen, tumor cell glucose metabolism will switch from oxidative phosphorylation to glycolysis. So far, pyruvate kinase (PK) has been regarded as an important regulator of the Warburg effect. PK can catalyze the dephosphorylation of phosphoenolpyruvate (PEP) to pyruvate and generate ATP, which is a rate-limiting step in glycolysis.
PK can be divided into four isozymes: PKM1, PKM2, L-PK and R-PK. According to different metabolic functions of tissues, they have significantly different regulatory mechanisms and dynamic characteristics. Among them, PKM1 and PKM2 are encoded by the PKM2 gene, and are produced by different alternative splicing of the precursor mRNA during transcription. During embryonic development, PKM2 was gradually replaced by PKM1. In contrast, L-PK or PKM1 isozymes are down-regulated and PKM2 is expressed again during tumorigenesis, indicating that PKM2 plays a unique role in cancer cells.
Because the enzyme activity of PKM2 is smaller than that of PKM1, it catalyzes and synthesizes more glycolysis intermediate products into building blocks of nucleic acids, amino acids and lipids. There is increasing evidence that some oncogenes reprogram glycolysis via PKM2, which affects tumor invasion phenotype. In addition, recent studies have also confirmed that PKM2 can be used as a transcription coactivator or protein kinase to promote gene transcription and tumor formation. However, the current PKM2 regulatory mechanism has not been fully elucidated.
In this new article, the researchers identified a known oncoprotein: serine / threonine protein kinase PIM2, a new binding partner protein of PKM2. Using multiple biochemical methods in vitro and in cultured cells, the researchers confirmed the interaction between PIM2 and PKM2. They found that PIM2 directly phosphorylates PKM2 on Thr454 residues, resulting in increased levels of PKM2 protein. Compared with the wild type, PKM2 with phosphorylation-deficient mutations showed a reduced effect on glycolysis, cell proliferation, and co-activation of HIF-1α and β-catenin, while cancer cell mitochondrial respiration increased.
These results confirm that PIM2-dependent PKM2 phosphate is essential for regulating the warburg effect in cancer, indicating that PIM2 is a potential therapeutic target.
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