Altered Metabolism of Four Compounds Drives Glioblastoma Growth

The altered metabolism of methionine, tryptophan, kynurenine, and 5-methylthioadenosine can drive the development of the most common and lethal form of brain cancer, glioblastoma. Results from this study also suggest ways to treat the cancer, slow its growth, and precisely elucidate its extent.¹

Glioblastoma cells lose key enzymes and that results in atypical metabolism of methionine, tryptophan, kynurenine, and 5-methylthioadenosine. The changed metabolism of methionine activates oncogenes. The altered metabolism of tryptophan allowed glioblastoma cells to evade detection by immune cells.

This study, published in Clinical Cancer Research, used liquid chromatography and mass spectrometry to discover and validate metabolites in glioblastoma cells and tissues and normal human astrocytes. Methionine, tryptophan, kynurenine, and 5-methylthioadenosine comprised a 4-metabolite signature of glioblastoma cells.

Compared with normal human astrocytes, glioblastoma cells’ aberrant metabolism of methionine concentrated the amino acid 5 to 100 times more. When glioblastoma cells were grown in the absence of methionine, tumor growth slowed 40% to 60%. In addition, aberrant methionine metabolism resulted in abnormal methylation and gene silencing, causing the expression of oncogenes.

Kynurenine and tryptophan are metabolized in the same pathway. Deregulation of the enzymes that metabolize kynurenine and tryptophan could allow glioblastoma cells to escape detection by the immune system.

“Our findings suggest that restricting dietary intake of methionine and tryptophan might help slow tumor progression and improve treatment outcomes,” stated Kamalakannan Palanichamy, PhD, research assistant professor in radiation oncology, the Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, and first author of the study.

Since glioblastoma cells take up methionine much more quickly than normal glioma cells, positron emission tomography using methionine as a tracer (MET-PET) could more accurately map glioblastoma tumors. More accurate mapping could enable better precision at surgical removal. MET-PET is currently an experimental imaging technique.

National Cancer Institute grants supported this research.

REFERENCE

1. Palanichamy K, Thirumoorthy K, Kanji S, et al. Methionine and kynurenine activate oncogenic kinases in glioblastoma, and methionine deprivation compromises proliferation [published online ahead of print March 2, 2016]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-2308.