Glycosylation Gives Growth Advantage to Hypoxic Tumor Cells

Tumors survive in a microenvironment characterized by low oxygen levels (hypoxia) by shifting the metabolism of their cells away from the glycolytic pathway used by normal cells and onto the alternative pentose phosphate pathway.

The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a process that generates NADPH and pentoses (five-carbon sugars). There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the nonoxidative synthesis of five-carbon sugars. This pathway is an alternative to glycolysis. While it does involve oxidation of glucose, its primary role is anabolic rather than catabolic. For most organisms, it takes place in the cytosol.

Investigators at the California Institute of Technology (Pasadena, USA; www.caltech.edu) studied the role of the regulatory enzyme phosphofructokinase 1 (PFK1) in the transition of cancer cells from the glycolytic pathway to the pentose phosphate pathway.

PFK1 is the most important control site in the mammalian glycolytic pathway. This step is subject to extensive regulation since it is the committed step - the first irreversible reaction unique to the glycolytic pathway. This leads to a precise control of glucose, galactose, and fructose going down the glycolytic pathway. Before this enzyme's reaction, glucose-6-phosphate can potentially travel down the pentose phosphate pathway, or be converted to glucose-1-phosphate for glycogenesis.

The investigators reported in the August 24, 2012, issue of the journal Science that the action of PFK1 was modified under hypoxic conditions by O-GlcNAcylation of the protein's amino acid serine located at position 529. This posttranslational addition of a sugar residue was orchestrated by O-linked beta-N-acetylglucosamine (O-GlcNAc).

Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo.

"We have identified a novel molecular mechanism that cancer cells have coopted in order to produce intermediates that allow them to grow more rapidly and to help them combat oxidative stress," said senior author Dr. Linda Hsieh-Wilson, professor of chemistry at the California Institute of Technology. "What is unique here is that the addition of GlcNAc is dynamic and reversible. This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters."

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