The Role of Metabolism in Cancer

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 bioenergetic demands.

CST antibody tools can help 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 the conversion of pyruvate to lactate. This shift to lactate production in the presence of oxygen is called 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.

Explore the interactive Warburg Effect Pathway Diagram, along with associated CST antibody products.  View the 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 intracellular pools, serves as a primary substrate for generating energy in the often poorly vascularized and nutrient-deprived tumor microenvironment (TME).
• Specific amino acid transporters enable glutamine to enter cells, where it is then converted to glutamate in the mitochondria. Glutamate 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 of 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.

Explore the interactive Glutamine Metabolism Pathway, along with associated CST antibody products.  View the pathway

Lipid Signaling and Cancer

Lipid signaling pathways are among the most frequently altered signal transduction systems 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 to an array of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs).
• Key signaling nodes in the PI3K pathway include the serine/threonine kinases AKT and mechanistic target of rapamycin (mTOR), which act on downstream effectors to regulate cell growth, proliferation, survival, and cellular metabolism.
• The Phosphatase and Tensin homolog (PTEN) serves as a brake for PI3K signaling. This tumor suppressor gene is frequently mutated in cancers, leading to hyperactivation of the PI3K pathway.
• Aberrant activation of the PI3K pathway is often associated with resistance to cancer therapies and tumor progression.

Explore the interactive Phosphoinositide (Lipid) Signaling Pathway, along with associated CST antibody products. View the pathway

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 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.

Explore the interactive AMPK Signaling Pathway, along with associated CST antibody products. View the pathway

• Both the gain and loss of AMPK signaling can promote 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 enable cell growth, proliferation, and the reprogramming of cancer cell metabolism.  
• 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.

Explore the interactive mTOR Signaling Pathway, along with associated CST antibody products. View the pathway

• As a central regulator of cell growth, proliferation, and protein synthesis, overactivation 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 overactivation of PI3K and AKT signaling contribute to the hyperactivation of mTOR in cancers.

Additional Metabolism Resources 

• Learn about the role of the immune system and metabolism in driving cancer in this blog: Interrogating Immunometabolism in the TME Using a Metabolic Checkpoint
• Read the Deregulating Cellular Metabolism blog, part of the Hallmarks of Cancer series, for a more in-depth look at the key biochemical and signaling pathways involved in oncogenesis.