Inhibition of Enzyme GLDC Could Kill Off Glioblastoma Cells

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Inhibition of Enzyme GLDC Could Kill Off Glioblastoma Cells
Inhibition of Enzyme GLDC Could Kill Off Glioblastoma Cells

Researchers from the Massachusetts Institute of Technology and the Whitehead Institute may have found a weakness in a subset of glioblastoma tumor cells that may help to develop more effective cancer treatments.

Dohoon Kim, PhD, of the Whitehead Institute, and colleagues found that the enzyme GLDC was of great importance to the survival of glioblastoma tumor cells, as it breaks down the amino acid glycine. Without the enzyme, metabolic byproducts build up inside the cells and they die off.

Further investigation revealed that GLDC was only overexpressed in glioblastoma cells with high levels of the gene SHMT2, which converts serine into glycine. SHMT2 is most highly-expressed in cancer cells found in ischemic regions at the center of tumors, where it influences the activity of PKM2, an enzyme that allows cells to generate new cancer cells. Overactive SHMT2 produces a significant amount of glycine, which the cell breaks down with GLDC.

The researchers believe that the lack of GLDC results in accumulated glycine, causing nonketotic hyperglycinaemia. The glycine is funneled through metabolic pathways that generate toxic molecules including aminoacetone and methylglyoxal.

On top of discovering the tumor cell vulnerability, the researchers made significant advancements in understanding how cancer cells alter metabolism to promote cell survival in poorly-vascularized ischemic tumor environments. Ultimately, cancer cells require SHMT2 for survival, but GLDC inhibition renders the cell environment toxic.

The researchers are now looking to identify a compound that blocks GLDC to be used as a new potential treatment for glioblastoma. 

References

  1. Kim D et al. Nature. 2015; doi:10.1038/nature14363.
  2. MIT press release
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