Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen1, 2. This metabolic signature (aerobic glycolysis or the Warburg effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation3, 4. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway5 (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.
At a glance
- Ueber den Stoffwechsel der Tumoren. Biochem. Z. 152, 319–344 (1924). , &
- On the origin of cancer cells. Science 123, 309–314 (1956).
- The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008). , , &
- Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009). , &
- 6th edn 577–589 (W. H. Freeman, 2006). , & Biochemistry
- Surfing the p53 network. Nature 408, 307–310 (2000). , &
- Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009). &
- Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005). et al.
- p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006). et al.
- p53 and metabolism. Nat. Rev. Cancer 9, 691–700 (2009). &
- Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998). et al.
- New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008). et al.
- A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999). et al.
- Novel human p53 mutations that are toxic to yeast can enhance transactivation of specific promoters and reactivate tumor p53 mutants. Oncogene 20, 3409–3419 (2001). &
- Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol. Cell Biol. 18, 7288–7293 (1998). &
- A leucine-rich nuclear export signal in the p53 tetramerization domain: Regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660–1672 (1999). et al.
- Characterization of functional domains necessary for mutant p53 gain of function. J. Biol. Chem. 285, 14229–14238 (2010). &
- Semirational design of active tumor suppressor p53 DNA binding domain with enhanced stability. Proc. Natl Acad. Sci. USA 95, 14675–14680 (1998). , , &
- Human glucose-6-phosphate dehydrogenase: The crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency. Structure 8, 293–303 (2000). , , &
- Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 94, 2955–2962 (1999). et al.
- Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127–1130 (2009). &
- TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006). et al.
- Critical role for Daxx in regulating Mdm2. Nat. Cell Biol. 8, 855–862 (2006). et al.
- Examination of primary metabolic pathways in a murine hybridoma with carbon-13 nuclear magnetic resonance spectroscopy. Biotechnol. Bioeng. 44, 563–585 (1994). , , , &
- A system for stableexpression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002). , &
- Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J. Biol. Chem. 273, 10609–10617 (1998). et al.
- A mutant-p53/Smad complex opposes p63 to empower TGF β-induced metastasis. Cell 137, 87–98 (2009). et al.
- Suppression of p53 activity by Siva1. Cell Death Differ. 16, 1493–1504 (2009). et al.
- A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J. Biol. Chem. 279, 20369–20377 (2004). et al.
- A method for determination of pyridine nucleotides using a single extract. Anal. Biochem. 285, 163–167 (2000). , &
- Supplementary Information (1M)