Cancer cells need a lot of energy to grow fast—to do so, they show abnormal metabolic pathways. Most mammalian cells use glucose as a fuel source. Glucose is metabolized by glycolysis in a multistep set of reactions, resulting in the creation of pyruvate. In typical cells under normal oxygen levels, much of this pyruvate enters the mitochondria, where it is oxidized by the Krebs Cycle to generate ATP to meet the cell’s energy demands.
However, in cancer cells or other highly proliferative cell types, much of the pyruvate from glycolysis is directed away from the mitochondria to create lactate through the action of lactate dehydrogenase (LDH/LDHA)—a process typically reserved for the low oxygen state. In contrast to mitochondrial glycolysis, lactate production in the presence of oxygen is termed “aerobic glycolysis” or the Warburg Effect. Several signaling pathways contribute to the Warburg Effect and other metabolic phenotypes of cancer cells. If you look at the pathway, you might notice PI3K/Akt, mTOR, Erk1/2 MAPK, ULK1 (Autophagy), p53, HIF1alpha, (Hypoxia - Angiogenesis), and AMPK all represented.
The Hallmarks of Cancer are seminal manuscripts by Doctors Robert Weinberg and Douglas Hanahan and were published in Cell1. The authors proposed the idea that the complexity of cancer can be broken down into smaller subsets of underlying principles. The information here pertains to one Hallmark of Cancer, known as "Deregulating Cellular Energetics." Other entries in this series explore the other proposed Hallmarks.
Cancer cells frequently use glutamine as another fuel source, which enters the mitochondria and can be used to replenish Krebs Cycle intermediates or to produce more pyruvate through the action of malic enzyme, or to produce building blocks to help the increased cell growth.
Cancer cells can become addicted to glutamine, with glutamine itself promoting cell proliferation. For this reason, glutamine metabolism is becoming a hot research area for cancer researchers. Because glycolysis is an intricate process, influenced by so many factors, there are many pathways to research. Check out some of these signaling players today.
Additional Resources
Read the additional blog posts in the Hallmarks of Cancer series to learn more:
- Resisting Cell Death
- Inducing Angiogenesis Energetics
- Sustaining Proliferative Signaling
- Enabling Replicative Immortality
- Evading Growth Suppressors
- Activation Invasion and Metastasis
- Tumor Promoting Inflammation
- Genome Instability and Mutation
- Avoiding Immune Destruction
Select References
- Hanahan D, Weinberg RA (January 2000). "The Hallmarks of Cancer". Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9
- Hanahan D, Weinberg RA (March 2011). "Hallmarks of Cancer: the next generation". Cell. 144 (5):646-74. doi: 10.1016/j.cell.2011.02.013
