Cancer Researchers Identify Enzyme That Enables Glucose-Independent Tumor Growth

Cancer researchers have identified an enzyme that allows tumor cells to exploit alternative energy sources in order to survive when sources of glucose have been depleted.

Investigators at McGill University (Montreal, Canada) and colleagues from several other research institutes used combined transcriptional-metabolomic network analysis to identify metabolic pathways that could support glucose-independent tumor cell proliferation.

They reported in the October 15, 2015, issue of the journal Molecular Cell that glucose deprivation stimulated rearrangement of the tricarboxylic acid (TCA or Krebs) cycle and early steps of the gluconeogenesis (glucose synthesis) pathway to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of the enzyme mitochondrial PEP-carboxykinase (PEPCK).

PEPCK is an enzyme that converts oxaloacetate into phosphoenolpyruvate and carbon dioxide. As PEPCK acts at the junction between glycolysis and the Krebs cycle, it causes decarboxylation of a four-carbon molecule, creating a three-carbon molecule. When GTP (guanosine-5'-triphosphate) is present, PEPCK decarboxylates and phosphorylates oxaloacetate for its conversion to phosphoenolpyruvate (PEP), which is the first committed step in gluconeogenesis. As a phosphate is transferred, the reaction produces a GDP (guanosine-5'-diphosphate molecule).

The investigators found that under conditions of glucose deprivation, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PEPCK expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo, as shown in a mouse model. Elevated PEPCK expression was observed in several human tumor types and was enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients.

"The fact that PEPCK levels are elevated in some cases of human lung cancer suggests that this enzyme may play a role in the human disease," said senior author Dr. Russell Jones, associate professor of physiology at McGill University. "Our work shows that cancers can use alternative fuel sources to help drive their growth under stressful conditions. This remarkable flexibility is part of what makes cancer so deadly, but offers hope in finding new therapies."

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