CancerQuest | Cancer: Running A Critical Cellular Pathway BACKWARDS!

Cancer cells grow in an unregulated manner. To be able to grow and divide, the cells need large amounts of energy and resources.

The Krebs cycle, also called the tricarboxcylic acid cycle (TCA), or citric acid cycle (CAC), is a central part of cell metabolism and normally provides cells with several useful products. This pathway takes in a breakdown product of glucose, called acetyl-CoA, and produces usable forms of energy (GTP) and other products (FADH and NADH₂) that can then go into mitochondria to produce more usable energy (ATP) or be used to build cell components.

In cancer cells, the Krebs cycle or the mitochondria are often defective, preventing the normal flow of events. Cancer cells must overcome this block to keep going. Recent research has demonstrated a surprising way that at least some cancer cells get the raw materials they need to build cell components.

The study used osteosarcoma and kidney cancer cells that had defective mitochondrial pathways and were therefore not able to complete the normal breakdown of glucose. Without a way around the block, the cells would not be able to make the building blocks of lipids and could not grow. What the researchers found really surprised them. The cancer cells were shown to be running the Krebs cycle backwards to get the products they needed.

The results help to explain how cancer cells are able to continue to divide, even when damaged, and because the process does not occur in normal cells, it also identifies a potential target for cancer treatment.

Bottom Line: Cancer cells require large amounts of energy and raw materials to continually grow and divide. When they are not able to use the normal systems, they can drive the citric acid cycle in reverse to obtain what they need.

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Original Article: Reductive carboxylation supports growth in tumour cells with defective mitochondria Andrew R. Mullen, William W. Wheaton, Eunsook S. Jin, Pei-Hsuan Chen, Lucas B. Sullivan, Tzuling Cheng, Youfeng Yang, W. Marston Linehan, Navdeep S. Chandel and Ralph J. DeBerardinis. Nature (Published online Nov. 20, 2011)