A new paper published in Molecular Cell(2014) by Zhimin Lu, Ph.D., professor of Neuro-Oncology at The University of Texas MD Anderson Cancer Center and colleagues, reports that PKM2 is vital to division and development of brain tumor cells.

The research shows that tumor cells rely heavily on a distinct mechanism for orderly cell division that’s driven by oncogene-induced pyruvate kinase M2(PKM2). After a cell begins division by replicating all of its chromosomes, mitosis separates them into two identical sets of chromosomes for both cells. If without PKM2 regulating a checkpoint in mitosis, the tumor cell would not successfully divide. Depleting PKM2 led to an uneven distribution of DNA to the two new cells, triggering programmed cell death, or apoptosis. The research also revealed that PKM2 phosphorylates a protein called Bub3, activating it to interact with others in a protein complex that assures orderly and equal chromosome separation. Depleting PKM2 blocked Bub3 activation, leading to an increase in cells with abnormal numbers of chromosomes and programmed cell death. The findings have been confirmed in human breast, prostate, lung, pancreatic and colon cancer cell lines.

The research further highlights the importance of PKM2 in human cancers and of developing ways to target its activity and use it as a biomarker to guide treatment.

Up to now, professor Zhimin Lu and his colleagues have now identified four specific mechanisms by which PKM2 promotes cancer development. The other three mechanisms respectively are: activating an important transcription co-factor that, in turn, activates other cancer-promoting genes; phosphorylating the histone protein H3, loosening the packaging of DNA and leading to the activation of cell division genes; Inducing expression of glycolytic genes (including PKM2 itself) and triggering a glucose metabolism mechanism called the Warburg effect that nourishes tumor cells.

Yuhui Jiang, Xinjian Li, Weiwei Yang, David H. Hawke, Yanhua Zheng, Yan Xia, Kenneth Aldape, Chongyang Wei, Fang Guo, Yan Chen, Zhimin Lu

Summary:
Tumor-specific pyruvate kinase M2 (PKM2) is instrumental in both aerobic glycolysis and gene transcription. PKM2 regulates G1-S phase transition by controlling cyclin D1 expression. However, it is not known whether PKM2 directly controls cell-cycle progression. We show here that PKM2, but not PKM1, binds to the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, where it interacts with Blinkin and is essential for correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint, accurate chromosome segregation, cell survival and proliferation, and active EGF receptor-induced brain tumorigenesis. In addition, the level of Bub3 Y207 phosphorylation correlated with histone H3-S10 phosphorylation in human glioblastoma specimens and with glioblastoma prognosis. These findings highlight the role of PKM2 as a protein kinase controlling the fidelity of chromosome segregation, cell-cycle progression, and tumorigenesis.