Oncogenes and Tumor Suppressors Reprogram Metabolism

Proliferating cells require the biosynthesis of structural components for biomass production and for genomic replication. This requires a reprogramming of the metabolic pathways to ensure nutrients such as glucose and glutamine are not completely oxidized but instead their intermediary metabolites are shunted into biosynthetic pathways. It is now well appreciated that multiple metabolic pathways can be reprogrammed during oncogenesis and that both oncogenes and tumor suppressors can induce this reprogramming to ensure metabolites are shunted into pathways that support the biosynthesis of structural components. In part, this is achieved by maintaining high rates of glycolysis, slowing pyruvate entry into the Tricarboxylic Acid (TCA) cycle, and utilizing TCA intermediates for biosynthetic precursors.1,2

Metabolic reprogramming is a feature of both oncogenic cells and non-transformed cells undergoing proliferation. However, in non-transformed cells, growth factor signaling-induced changes to metabolism are sensitive to environmental cues and quickly downregulated if conditions are unfavorable. In cancer cells, these pathways become uncoupled from both growth factor-induced stimulation and from the negative regulation that typically halts proliferation when environmental conditions become unfavorable. This uncoupling is due to the driver effects of oncogenes and/ or the loss of negative regulation via the inactivation of tumor suppressors.3 Because many of these reprogramming events seem to be commonly used amongst various tumor types, modulation of these metabolic pathways may be an Achilles’ heel that can be exploited for therapeutic purposes.

The switch to aerobic glycolysis that occurs in many tumor cells, named the Warburg effect, has been appreciated for decades. It is now known that many cancer cells rely primarily on glycolysis for the generation of ATP and for the creation of metabolic intermediates to shunt into biosynthetic pathways.1,2 In non-proliferatively active cells, glucose is metabolized by glycolysis to pyruvate which enters the TCA cycle as acetyl-CoA. Within the TCA cycle and subsequent oxidative phosphorylation, the acetyl-CoA is oxidized to CO2 and water, generating 32-34 ATP molecules. During proliferation, cells increasingly rely on glycolysis for ATP generation and divert much of the pyruvate from the TCA cycle through conversion to lactate which is secreted from the cell. The conversion of pyruvate to lactate by lactate dehydrogenase (LDH), a transcriptional target of oncogenic signaling, regenerates one NAD+ for use in glycolysis. The rapid removal of pyruvate via lactate conversion allows the cell to maintain high rates of glycolytic flux by both removing excess pyruvate and through the regeneration of NAD+.1

Many of the well characterized oncogenes, for example PI3K, AKT, c-Myc, and RAS, promote glycolysis while tumor suppressors tend to inhibit glycolysis.4 For example, the p53 tumor suppressor negatively regulates the expression of the glycolytic protein phosphoglycerate mutase-2 (PGM2) and promotes the expression of Tumor Protein 53-Induced Glycolysis and Apoptosis Regulator (TIGAR), which depletes the glycolytic activator 2,6-fructose biphosphate.5 Oncogenic signaling through the PI3K/Akt pathway, commonly upregulated in cancer, promotes glycolysis by multiple mechanisms. Akt signaling increases the expression and membrane localization of glucose transporters and increases the activity of glycolysis enzymes such as phosphofructokinase and hexokinase 2. The product of hexokinase 2, glucose-6-phosphate, can also be diverted to the pentose phosphate pathway (PPP) to support the production of NADPH for use in fatty acid synthesis and ribose-5-phosphate for nucleotide synthesis. Akt signaling can also increase the activity of Hypoxia Inducible Factor-1 (HIF1), another potent inducer of glycolysis. Upregulation of HIF activity, by PI3K, hypoxia, or the loss of the von Hippel- Lindau tumor suppressor that targets HIF for degradation, results in the transcriptional upregulation of multiple genes involved in glycolysis and the decreased entry of pyruvate into the TCA cycle.6 PI3K signaling also regulates mTOR activity by phosphorylating and inhibiting TSC which, along with LKB1, negatively regulates mTOR activity. mTOR is a key node for integrating signals such as cellular stress and nutrient availability with proliferation. In line with this, mTOR is also negatively regulated by signaling through the bioenergetic sensor and metabolic checkpoint protein, AMP-Activated Protein Kinase (AMPK). AMPK is activated when the AMP/ATP ratio is increased, and signaling through AMPK inhibits proliferation and promotes increased oxidative phosphorylation to restore ATP levels. AMPK is regulated by the tumor suppressor protein LKB1, and loss of LKB1 is sufficient to promote tumorigenesis.7 Loss of LKB1 is associated with decreased AMPK signaling and enhanced activation of mTOR. This suggests agonists that restore AMPK signaling, such as metformin and phenformin, may have antitumor activity.

Myc reprograms cellular metabolism through transcriptional regulation and is often overexpressed in many cancers. Myc overexpression results in increased dependence and utilization of glutamine. Glutamine is the nitrogen donor that can be used for the synthesis of nucleotides and for TCA anapleurosis, the regeneration of TCA cycle intermediates diverted for use in biosynthetic reactions. Enhanced Myc activity promotes increased glutamine uptake via the upregulation of the glutamine transporters SLC5A1 and SLC7A1. Myc also promotes increased glutaminase 1 levels, supporting glutaminolysis.8 Myc enhances glycolysis by increasing glucose uptake, upregulating the expression of lactate dehydrogenase, and favoring the production of the M2 isoform of pyruvate kinase (PKM2), a key regulator of glycolytic flux. Pyruvate kinase catalyzes the last step in glycolysis, the dephosphorylation of phospho(enol)pyruvate to pyruvate. In cancer cells, PKM2 is almost always in the inactive form. This results in the build-up of glycolytic intermediates which are shunted into other biosynthetic pathways such as the PPP. Understanding and unraveling the mechanisms by which oncogenes and tumor suppressors regulate metabolism will be key to developing new therapeutic targets.


Immunofluorescence of HUVEC cells

Anti-VHL (1-15): Cat. No. V0140: Immunofluorescence of HUVEC cells using VHL (1-15) (RB),Cat. No. V0140 (red) at a 1:800 dilution, taken at 40× magnification and nuclear staining with Hoescht 33342 (blue). Yale HTCB IF procedure used.

Immunofluorescence of NIH-3T3 cells

Anti-LKB1 : Cat. No. SAB4502888: Immunofluorescence of NIH-3T3 cells using Anti-LKB1 antibody. Cells on the left were treated with the Anti-LKB1 antibody. Cells on the right (negative control) were treated with both Anti-LKB1 antibody and the synthesized immunogen peptide.

Immunofluorescence of HUVEC cells

Anti-PIK3CG (101-115) (RB): Cat. No. K3641: Immunofluorescence of HUVEC cells using PIK3CG (101-115) (RB), Cat. No. K3641 (red) at a 1:100 dilution, taken at 40× magnification and nuclear staining with Hoescht 33342 (blue). Yale HTCB IF procedure used.

Monoclonal Anti-AKT1

Monoclonal Anti-AKT1, antibody produced in mouse, clone 6D6, purified immunoglobulin: Cat. No. SAB1400005: Antibody concentration: 3.0 μg/mL using human human colon tissue.




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  3. Kaelin, W. G. and Thompson, C. B. Q&A: Cancer: Clues from Cell Metabolism. Nature, 465, 562-564 (2010).
  4. Munoz-Pinedo, C. et al. Cancer Metabolism: Current Perspectives and Future Directions. Cell Death and Disease. e248 (2012).
  5. Bensaad, K. et al. TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis. Cell, 126, 107-120 (2006).
  6. Cairns, R.A. et al. Regulation of Cancer Cell Metabolism. Nature Rev. Cancer, 11, 85-95 (2011)
  7. Shaw; RJ. LKB1 and AMPK Control mTOR Signaling and Growth. Acta Physiol (OXF). 196, 65-80 (2009).
  8. Wise, D. R. and Thompson, C. B. Glutamine Addiction: A New Therapeutic Target in Cancer. Trends Biochem Sci, 35, 427-433 (2010).


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