Study uncovers vital Warburg effect pathway in brain tumour formation and metabolism.

In oncology, the Warburg effect is the observation that that the driver of tumourigenesis is an insufficient cellular respiration caused by insult to mitochondria.  It postulates that most cancer cells, instead of fully respiring in the presence of adequate oxygen, ferment instead.  Therefore, the Warburg effect promotes tumour progression; exactly how this is coordinated remains elusive.  Now, a study from researchers led by The University of Texas shows that PGK1, a glycolytic enzyme, plays a role in coordinating cellular processes crucial to cancer metabolism and brain tumour formation, shedding further light on the Warburg effect. The team state that their findings may lay the groundwork for improved approaches to diagnosis and treatment of glioblastoma and other cancers.  The study is published in the journal Molecular Cell.

Previous studies show that normal cells generate oxygen for survival via a relatively low rate of glycolysis, which converts glucose into the enzyme pyruvate. Pyruvate is used in the citric acid cycle (TCA), a series of chemical reactions that generate energy.  Cancer cells, however, produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cell, a process that converts glucose into cellular energy and forms lactic acid.  Thus, the Warburg effect is characterized by increased levels of glucose, lactate production and suppression of pyruvate metabolism in mitochondria.  Exactly how this process is coordinated with cancer metabolism has been little understood.  The current study sheds further light on the Warburg effect by showing that PGK1 acts as a protein kinase in coordinating glycolysis and the TCA cycle, which is instrumental in cancer metabolism and tumourigenesis.

The current study shows that PGK1 is instrumental in glycolysis and the citric acid cycle, both important for generating the energy that feeds cancer cells. Results shows that PGK1 acts as a protein kinase in coordinating glycolysis and the citric acid cycle in cancer metabolism and tumour formation.  Data findings show that a cellular chain of events involving activation of cancer genes like EGFR, KRAS and B-Raf and the protein ERK, allowed PGK1 to translocate into the cell’s mitochondria.

The lab explain that mitochondria are membrane-containing cell components crucial for producing energy. They go on to add that PGK1 acts as a protein kinase in mitochondria and activates a critical enzyme that inhibits the mitochondria’s ability to use pyruvate, suppressing chemically reactive molecules containing oxygen and increased lactate levels.

The team surmise that their findings provide critical insight into the Warburg effect and demonstrates that PGK1 ultimately promotes cancer cell proliferation and tumour formation.  For the future, the researchers state that their study may help in the development of a molecular basis for improved diagnosis and treatment of cancer.

Source: The University of Texas MD Anderson Cancer Center