Tumor Suppression Through Metabolic Regulation

Science Signaling  27 Apr 2010:
Vol. 3, Issue 119, pp. ec126
DOI: 10.1126/scisignal.3119ec126

The tumor suppressor p53 is a transcriptional regulator that serves both to eliminate damaged cells and to protect cells from damage under periods of stress (see Vousden). Because of its critical roles, mutations that reduce p53 function are common in many cancers. Another hallmark of many cancers is their altered metabolism such that the transformed cells rely on glycolysis, rather than oxidative phosphorylation, for energy. Hu et al. and Suzuki et al. identified the gene encoding a mitochondrial glutaminase, GLS2, as a target for p53 and showed through chromatin immunoprecipitation experiments that p53 bound to the promoter. Cells with wild-type p53 exhibited greater abundance and transcription of GLS2 compared with cells either genetically deficient in p53 or in which p53 was knocked down. Both groups found that specific stresses that activated p53 increased GLS2 abundance in cells with functional p53 but not in those deficient for p53. GLS2 catalyzes the mitochondrial conversion of glutamine to glutamate, and overexpression of GLS2 increased the concentration of glutamate. Glutamate is a precursor for intermediates in the Krebs cycle and thus contributes to oxidative phosphorylation. Hu et al. found that cells in which GLS2 was overexpressed exhibited increased oxygen consumption and that cells deficient for p53 or in which GLS2 was knocked down exhibited reduced oxygen consumption. Glutamate is also the precursor of the antioxidant molecule glutathione, and both groups found that overexpression of GLS2 increased the ratio of reduced to oxidized glutathione (GSH/GSSG) and reduced the abundance of (Hu et al.) and damage caused by (Suzuki et al.) reactive oxygen species (ROS). Furthermore, overexpression of GLS2 protected cells from ROS-induced apoptosis (Hu et al.) or from DNA damage caused by daunorubicin (Suzuki et al.). GLS2 is abundant in the liver, so both groups analyzed whether there was a correlation between GLS2 abundance and liver cancer. Both groups found that the abundance of GLS2 transcripts was decreased in cancer cells compared with that in adjacent normal tissue or compared with that in liver tissue exhibiting hepatitis or other noncancerous diseases. Thus, another mechanism by which p53 supports cell survival and prevents tumorigenesis is by controlling cellular metabolism through the induction of genes involved in regulation of metabolic processes.

W. Hu, C. Zhang, R. Wu, Y. Sun, A. Levine, Z. Feng, Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl. Acad. Sci. U.S.A. 107, 7455–7460 (2010). [Abstract] [Full Text]

S. Suzuki, T. Tanaka, M. V. Poyurovsky, H. Nagano, T. Mayama, S. Ohkubo, M. Lokshin, H. Hosokawa, T. Nakayama, Y. Suzuki, S. Sugano, E. Sato, T. Nagao, K. Yokote, I. Tatsuno, C. Prives, Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl. Acad. Sci. U.S.A. 107, 7461–7466 (2010). [Abstract] [Full Text]

K. H. Vousden, Alternative fuel—Another role for p53 in the regulation of metabolism. Proc. Natl. Acad. Sci. U.S.A. 107, 7117–7118 (2010). [Abstract] [Full Text]