A New "Glyco" Target for Cancer

 

 

 

 

 

24Aug12

    A research team at CalTech has found that post-translational modification of phosphofructokinase 1 (PFK1), an enzyme that normally acts to regulate glycolysis, by adding O-linked β-N-acetylglucosamine (O-GlcNAc) in the cytosol, affects cancer cell survival. This occurs because PFK 1 can "dictate" the mechanisms the cells employ to respond to environmental cues such as hypoxia. A dynamically changing microenvironment is typical for tumors and hypoxic states are a common feature for growing tumors as well as a barrier to disease progression.

 

     O-GlcNAcylation is a well-known "nutrient sensor" that links metabolic status to the regulation of intracellular signaling pathways. O-GlcNAcylation of intracellular proteins in the cytoplasm is itself a rapid and dynamic process and previous studies have shown that silencing the enzyme that adds GlcNAc to intracellular proteins [from UDP-GlcNAc] inhibits tumor growth in breast cancer and prostate cancer metastasis [please see this overview]. However, the functional consequences of dynamic O-GlcNAcylation in the regulation of cell metabolism have, to date, remained largely unknown

 

     PFK1 is an important control point for cellular responses to environmental stress given its central role in regulating glycolysis (the conversion of glucose to energy in the form of ATP). Higher PFK1 activity leads to a higher glycolytic flux whereas lowering PFK1 activity shunts glucose to alternative metabolic routes, namely the pentose phosphate [PP] pathway. The PP pathway produces pentose sugars as raw materials for nucleotide and nucleic acid biosynthesis, as well as NADPH to counter oxidative stress, for example during hypoxia. For cancer cells, the ability to choose between more glucose and more pro-proliferation building blocks is important for survival and growth.

 

     Much is already known about the biochemical regulation of PFK1 and thus regulation of activity through O-GlcNAcylation is all the more surprising. PFK 1 is modulated by intracellular kinases and is inhibited through metabolic pathway "end products" such as ATP, citrate, and lactate while the enzyme can be activated by AMP and fructose-2,6-bisphosphate [ coming home!...I was part of the team that discovered this activator of PFK 1 while at Vanderbilt University].The cellular levels of fructose 2,6-bisphosphate are exquisitvely controlled through the actions of another enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFK 2). PFK 2 is a bifunctional enzyme that both synthesizes and degrades fructose 2,6-bisphosphate and specific isoforms of PFK 2 do one job better than the other, thus affecting the cellular activity of PFK 1.

 

     Reporting the in the journal Science, the CalTech team found that the addition of O-GlcNAc to PFK 1 at position Ser-529 inhibited enzyme activity (there are many examples of protein glycosylation reducing the intrinsic activity of enzymes) and consequently  "... reduced cancer cell proliferation in vitro and impaired tumor formation in vivo." Thus, "...[t]hese studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention." And, as noted in the accompanying Perspective, "...Unlike most metabolic changes reported in cancer, this mode of regulation appears to be tumor specific. "