News Headline: MD Anderson Researcher Reveals Cancer Promoting Protein Is Vital to Safe Division of Tumor Cells
Outlet Full Name: Bio News Texas
Author: Susan Andizzoni
New research by Zhimin Lu, Ph.D., professor of Neuro-Oncology at The University of Texas MD Anderson Cancer Center, and colleagues have discovered how a tumor-specific protein turns on a critical switch in an irregular mechanism for mitosis that allows cancer cells to divide safely. Lu comments, “Our 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)”. Once a cell begins division by replicating its genetic material, mitosis separates the cell into two identical daughter cells. Once mitosis is done, cytokinesis finishes cell division.
Lu comments, “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, of those cells after division. This new, additional role for PKM2 in cancer development and survival may provide a molecular basis for diagnosing and treating tumors with upregulated PKM2”. The relationship between PKM2 activity and mitosis found by the researchers led to rapid tumor growth when activated in mice, while blocking it reduced tumor volume by 83 percent and more than doubled survival from about 20 days to beyond 40 days.
Fifty human glioblastoma multiforme tumors and 50 lung cancer tumors were analyzed and this conformed the relationship in human cancer and indicated an effect on survival for individuals with glioblastoma. Glioblastoma is the most common and lethal form of brain tumor.
PKM2 is a phosphorylating protein that activates other proteins by attaching phosphate groups to them. PKM2 plays a normal role in sugar metabolism and it promotes cell growth during infancy when growth is desired. Lu notes, PKM2 usually turns off eventually, but tumor cells have the ability to reactivate it. The tumor-specific PKM2 is activated by epidermal growth factor receptor (EGFR) which happens to be overactive in a number of cancers. If you deplete PKM2 in mitosis, tumor cells abnormally divide in a number of cancer types.
Researchers carried out a series of experiments in glioblastoma cell lines and this revealed that PKM2 phosphorylates a protein known as Bub3. Activating Bub3 interacts with other proteins to from a complex that brings about orderly and equal chromosome separation. By depleting PKIM2, Bub3 activation is blocked. This leads to an increase in cells with abnormal numbers of chromosomes and apoptosis. Researchers confirmed their findings in human breast, prostate, lung, pancreatic and colon cancer cell lines. Experiments on the glioblastoma and lung cancer tumors confirmed that phosphorylation of Bub3 correlates with phosphorylation of H3-S10. H3-S10 is a marker of cell mitosis in tumor cells.
When phosphorylation of Bub3 is low, glioblastoma individuals live longer. Of the 50 glioblastoma individuals, those with low levels of Bub3 phosphorylation (15 patients) had a median survival of almost 70 weeks as compared to a little over 40 weeks for the other 35 individuals with Bub3 activation.
Earlier research by Lu and colleagues demonstrated PKM2, generally active outside of the nucleus, goes into the nucleus where it promotes cancer formation, growth and survival. PKM2 activates a transcription co-factor that activates other cancer-promoting genes. A histone protein H3 is then phosphorylated which leads to activation of cell division genes. This leads to induction of glycolytic genes (including PKM2 itself) and triggers a glucose metabolism mechanism known as Warburg effect that feeds tumor cells.
There are two current possibilities to thwart these effects and that includes two classes of drugs that inhibit SRC and MEK activity. Lu notes, “Our 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.”