Energy metabolism in Cancer cells?

Question

The TCA cycle intermediate Isocitrate dehydrogenase commonly undergoes point mutations in cancers. This allows IDH to reduce a-Ketogluterate to 2Hydoxygluterate, causing a reduction in pVHLs ability to hydroxylate HIF-1a, and a subsequent accumulation of HIF-1a. This leads to angiogenesis via VEGF. If the cancer cell is converting its a-KG away form the TCA cycle, how does the cell make up for the loss of TCA function, and subsequent ETC function for energy production? Why would the cancer cell prefer to lose high yield energy production in exchange for low yield energy production?

Answer 1

To partially answer your question, let's revisit the core pathology of Neoplasms.

According to pathologists, cancer has eight hallmarks which are common to most cancers. They are:

1. Genome Instability and Mutation
2. Inducing Angiogenesis
3. Resisting Cell Death
4. Deregulating Cellular Energetics
5. Sustaining Proliferative Signaling
6. Avoiding Immune Destruction
7. Evading Growth Suppressors
8. Enabling Replicative Immortality
9. Tumor-Promoting Inflammation
10. Activating Invasion and Metastasis

One of the key features of cancer is the drastic uptake of glucose and glutamate and the rapid conversion of glucose to lactose; this is known as the Warburg effect. As you noticed, alpha-ketoglutarate, a main intermediate of the TCA cycle, is shunted and used for conversion by the mutated IDH to 2-hydroxyglutarate. The 2-hydroxyglutarate is an inhibitor to the TET family, which are regulatory enzymes responsible for the epigenetic regulation, which will cause the cell to become more proliferative and become more characteristic of a cancer cell.

This essentially causes rapid proliferation, which will require more nutrients and precursors for anabolic activity. Hence, the Warburg effect. The Warburg effect explains that the cancer cell receives most of its anabolic precursors from aerobic glycolysis, and the TCA cycle. An important point here is that the cancer cells do not prefer to lose the high-yield energy production, but that this is rather a process secondary to oncological metabolism.

This metabolism will, however, deplete the TCA cycle of its intermediates necessary for the oxidative reactions, as you mentioned. The cell will replenish most of its TCA cycle intermediates with glutamine in a process known as anaplerosis. Glutamine will be broken down via glutaminolysis and form alpha-ketoglutarate.

Also, keep in mind that there are three forms of Isocitrate Dehydrogenase; IDH1, IDH2, and IDH3.

All answers adopted from Robbin's Basic Pathology by Kumar et al. and The Molecular Basis of Cancer 4th Ed. by Saunders et al.