Sweetening of glutamine metabolism in cancer cells by Rho GTPases through convergence of multiple oncogenic signaling pathways

More than 60 years ago, Otto Warburg showed that cancer cells exhibit enhanced glycolysis accompanied by greatly elevated levels of lactate secretion, even in the presence of normal levels of oxygen (1). Warburg suggested that cancer cells arise from normal cells in a two-phase process: phase 1 is “injury” to the respiratory machinery (i.e., mitochondria), followed in phase 2 by enhanced “fermentation” (i.e., production of lactate from glucose) in the protoplasm (i.e., cytosol) (1). Conversion of glucose to lactate as a source of ATP is very inefficient compared to that obtained by complete oxidation of glucose to CO2 via tight coupling of glycolysis to the mitochondrial TCA cycle. Nevertheless, Warburg suggested that given ready access to adequate circulating glucose “fermentation” can provide quiescent cancer cells with the necessary energy requirements (1). For many years the Warburg effect was treated mainly as just another interesting biochemical phenomenon. However, within the last decade the “Warburg effect” has become the subject of intense investigation. We now know that the mitochondria in many cancer cells are not grossly defective as originally envisaged by Warburg, but are metabolically reprogrammed (2). In this case, the carbon of certain metabolites can enter the TCA cycle (anaplerosis) as both an energy source and as a source of intracellular components (e.g., for lipids, nucleic acids, proteins) necessary for rapidly dividing cells. An especially important metabolite in this regard is glutamine (3). Rapidly dividing cancer cells that require substantial amounts of glutamine are said to exhibit “glutamine addiction”. Glutamine is readily converted to the TCA cycle intermediate α-ketoglutarate (α-KG) while at the same time providing nitrogen for DNA, polyamine and non-essential amino acid synthesis. Glutamine is converted to α-KG in a two-step process. Glutamine is hydrolyzed to glutamate by glutaminase, which in turn is converted to α-KG by the glutamate dehydrogenase reaction or by transamination with a suitable α-keto acid substrate (4)