The glycosylation of a regulatory enzyme involved in keeping cells topped up with nutrients could represent a new target for cancer therapy, scientists claim. A team led by California Institute of Technology researchers has found that cancer cell survival is linked to the way the cells respond to environmental cues such as hypoxia by specifically adding O-linked β-N-acetylglucosamine (O-GlcNAc) to phosphofructokinase 1 (PFK1), an enzyme that normally acts to regulate glycolysis.
The post-translational glycosylation effectively inhibits the enzyme’s activity, suppressing glycolysis and redirecting metabolic flux down the oxidative pentose phosphate pathway to provide the cancer cells with pentose sugars for nucleotide and nucleic acid biosynthesis, as well as NADPH to combat oxidative stress. Essentially it’s a trade-off that increases survival chances, explain Linda C. Hsieh-Wilson, Ph.D., Wen Yi, Ph.D., and colleagues. The tumor cells produce less glucose, but are provided with a rich supply molecules required for growth and survival. “What’s unique here is that the addition of GlcNAc is dynamic and reversible,” comments Hsieh-Wilson. This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters.
The researchers found that GlcNAcylation of PFK1 was elevated two- to four-fold in a range of human tumors when compared with normal tissue. In vitro studies subsequently showed that blocking PFK1 glycosylation reduced cancer cell proliferation. And more importantly, the team went on to confirm that mice transplanted with human lung cancer cells that carried a glycosylation-defective PFK1 exhibited decreased tumor growth when compared with mice given wild-type lung cancer cells.
Reporting their work in Science, the team says this in vivo observation indicates that it may be possible to develop an anticancer strategy based on either blocking PFK1 glycosylation, or activating PFK1 to prevent cancer cells from switching their metabolic pathways. “Our results suggest that dynamic physiological inhibition of PFK1 may be a major regulatory point for central carbon flow ... Blocking PFK1 glycosylation to enhance its activity and reset cellular metabolism toward normal cell growth could therefore provide a new strategy to combat cancer.” Dr. Hsieh-Wilson et al., describe their findings in a paper titled “Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism.”