Glutaminase: a hot spot for regulation of cancer cell metabolism?

Abstract

Cancer cells re-program their metabolic machinery in order to satisfy their bioenergetic and biosynthetic requirements. A critical aspect of the re-programming of cancer cell metabolism involves changes in the glycolytic pathway (referred to as the "Warburg effect"). As an outcome of these changes, much of the pyruvate generated via the glycolytic pathway is converted to lactic acid, rather than being used to produce acetyl-CoA and ultimately, the citrate which enters the citric acid cycle. In order to compensate for these changes and to help maintain a functioning citric acid cycle, cancer cells often rely on elevated glutamine metabolism. Recently, we have found that this is achieved through a marked elevation of glutaminase activity in cancer cells. Here we further consider these findings and the possible mechanisms by which this important metabolic activity is regulated.

Keywords: cancer; glutaminase; metabolism.

Figure 1:. Metabolic remodeling of cancer cells Schematic highlights key differences in many cancer cells compared to normal tissue

Normal cells use glycolysis prior to respiration in the mitochondria (yellow) and complete breakdown of glucose by the tricarboxylic acid (TCA) cycle (green). In cancer cells, glycolysis becomes the primary mode of glucose metabolism resulting in lactate and its secretion. The M2 isoform of pyruvate kinase (PKM2) becomes tyrosine phosphorylated and attenuates pyruvate acetyl-CoA conversion while glutaminolysis provides the cancer cell with an alternate source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived a-keto-glutarate. The anti-tumor drug 968 inhibits glutamine metabolism by inhibiting the enzyme glutaminase (GLS).

Figure 2:. Glutaminase inhibition prevents Rho GTPase driven transformation

NIH-3T3 mouse fibroblasts in 10 cm plates were transfected with pZIPneoDbl and allowed to grow for 10 days in the presence of DMSO only (control), 5 M of the inactive 968 analog 335 (CAS registry number 22949-42-4), or 5 M 968 (CAS registry number 311795-38-7), after which the plates were fixed and stained with crystal violet. Structures of the inactive and active compounds are shown below treated cell samples.