CST BLOG: Lab Expectations

The official blog of Cell Signaling Technology (CST) where we discuss what to expect from your time at the bench, share tips, tricks, and information.

The Role of Metabolism in Cancer

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Alterations in the cellular metabolism of malignant cells have long been a central focus of cancer research. Tumor cells have adapted a multitude of novel mechanisms for the acquisition of nutrients and the reprogramming of metabolic pathways to meet their increased bioenergetics demands. CST provides helpful tools to detect and measure key metabolic changes in cancer cell biology.

The Warburg Effect, Glycolysis and Cancer

The Warburg effect is a metabolic adaptation thought to promote the uncontrolled proliferation and enhanced survival of many types of cancer cells.

  • In contrast to normal cells where energy is primarily produced via oxidative respiration in the mitochondria under normoxic conditions, cancer cells exhibit a high rate of glycolysis followed by conversion of pyruvate to lactate. This shift to lactate production in the presence of oxygen is termed “aerobic glycolysis” or the Warburg effect.
  • A dimeric form of the pyruvate kinase isoenzyme M2 (PKM2) is thought to play a central role in the Warburg effect.

Warburg Effect Interactive Signaling Pathway

Glutamine Metabolism and Cancer

The amino acid glutamine serves as an important metabolic fuel for rapidly proliferating cells. In fact, many cancer cells are reliant on glutamine to meet increased energy demands, and as such glutamine metabolism has emerged as an important therapeutic target in the treatment of cancer.

  • Glutamine, the most abundant free amino acid in circulation and in intracellular pools, serves as a primary substrate to generate energy in the often poorly vascularized and nutrient-deprived tumor microenvironment.
  • Specific amino acid transporters enable glutamine to enter cells where it is then converted to glutamate in the mitochondria which serves as a precursor to the TCA cycle intermediate a-ketoglutarate.
  • The isocitrate dehydrogenase enzymes (IDH1 and IDH2) play a central role in glutamine metabolism by catalyzing the reversible oxidative decarboxylation of isocitrate to yield a-ketoglutarate. Mutations in both IDH1 and IDH2 have been linked to the metabolic reprogramming observed in a variety of cancers.
  • Inhibitors to the mitochondrial enzymes glutaminase (GLS) and glutamate dehydrogenase (GDH), which block the conversion of glutamine to glutamate and catalyze the formation of a-ketoglutarate respectively, are currently being investigated in clinical trials to treat a range of malignancies.

Glutamine Metabolism Interactive Signaling Pathway

Lipid Signaling and Cancer

Lipid signaling pathways are among the most frequent signal transduction systems altered in cancer cells. In particular, the phosphoinositide 3- kinase (PI3K) pathway serves as a critical link between multiple receptor classes and downstream oncogenes to affect cellular function.

  • Three classes of PI3Ks have been identified, but PI3K class I is most commonly linked to cancer.
  • PI3Ks are activated in response by an array of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs).
  • Key signaling nodes in PI3K pathway include the serine/threonine kinases AKT and mTOR which act on downstream effectors to regulate cell growth, proliferation, survival, and cellular metabolism.
  • The Phosphatase and Tensin homolog (PTEN) serves as brake for PI3K signaling. This tumor suppressor gene is frequently mutated in cancers, leading to hyper-activation of the PI3K pathway.
  • Aberrant activation of the PI3K pathway is often associated with resistance to cancer therapies and tumor progression.

Phosphoinositide (Lipid) Signaling

Metabolic Signaling and Cancer

Metabolic adaptations found in cancer cells are often linked to alterations in primary metabolic signaling pathways. The most prominent examples include changes in the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) signaling networks which serve coordinate and independent functions.

  • AMPK is a master regulator of cellular energy and redox homeostasis that responds to diverse metabolic stress signals, including hypoxia, oxidative stress, and nutrient starvation, to stimulate the replenishment of cellular ATP supplies.
  • Both gain and loss of AMPK signaling can positively affect tumor cell growth and survival. First, AMPK activation provides tumor cells with the ability to adapt to metabolic stress. Conversely, loss of AMPK signaling can enhance the effects of oncogenic drivers, namely the tumor suppressors found in the AMPK signaling network LKB1, TSC2, and P53, to promote cell growth, proliferation, and the reprogramming of cancer cell metabolism.  
  • The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase present in two distinct intracellular signaling complexes (mTORC1 and mTORC2). In addition to responding to receptor tyrosine activation by numerous growth factors, mTOR is a major cellular nutrient sensor.
  • As a central regulator of cell growth, proliferation, and protein synthesis, over-activation of mTOR has been shown to significantly contribute to the development and growth of many cancers. Key mutations resulting in the loss of PTEN function or the over activation of PI3K and AKT signaling contribute to the hyper-activation of mTOR in cancers.

AMPK Interactive Signaling Pathway

 

mTOR Interactive Signaling Pathway

Learn more about cellular metabolism in this guide.

Chris Sumner
Chris Sumner
Chris Sumner was the Editor-in-Chief of Lab Expectations. When he's not reading/writing about curing disease, he's hiking in the woods, playing guitar, or searching for the world's best lobster roll.

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