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Suppressing tumors by pulling the plug on glycolysis

Date:
February 24, 2014
Source:
The Rockefeller University Press
Summary:
Cancer cells have long been known to have higher rates of the energy-generating metabolic pathway known as glycolysis. This enhanced glycolysis is thought to allow cancer cells to survive the oxygen-deficient conditions they experience in the center of solid tumors. Researchers reveal how damaged cells normally switch off glycolysis as they shut down and show that defects in this process may contribute to the early stages of tumor development.

Mouse cells fail to thrive in suspension cultures when wild-type Mdm2 is expressed (left), but expression of a mutant form of Mdm2 (right), in combination with PGAM and an oncogenic protein called Ras, enhances glycolysis and promotes cell transformation (right).
Credit: Mikawa et al., 2014

Cancer cells have long been known to have higher rates of the energy-generating metabolic pathway known as glycolysis. This enhanced glycolysis, a phenomenon known as the Warburg effect, is thought to allow cancer cells to survive the oxygen-deficient conditions they experience in the center of solid tumors. A study in The Journal of Cell Biology reveals how damaged cells normally switch off glycolysis as they shut down and shows that defects in this process may contribute to the early stages of tumor development.

Various stresses can cause cells to cease proliferating and enter an inactive state known as "senescence" that prevents their transformation into tumor cells. In 2005, Hiroshi Kondoh and colleagues found that cells normally limit glycolysis as they enter senescence and that increasing the levels of the glycolytic enzyme PGAM can prevent cells from exiting the cell cycle. PGAM is increased in many tumors, stimulating glycolysis and other important pathways. But how cells regulate PGAM has been unclear.

Working at Kyoto University in Japan, Kondoh and colleagues followed up on their previous work and found that, in response to DNA damage or oncogene expression, PGAM was degraded, thereby inhibiting glycolysis as the cells entered senescence. The enzyme Mdm2 targeted PGAM for degradation in response to these senescence-inducing stresses.

"Mdm2 can clearly, in some cases, act as a tumor suppressor by destabilizing PGAM," says Kondoh. Recent studies have emphasized the importance of PGAM as a therapeutic target for cancer management. Identifying the modulators of PGAM stability might open up new avenues for intervention.


Story Source:

The above story is based on materials provided by The Rockefeller University Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. T. Mikawa, T. Maruyama, K. Okamoto, H. Nakagama, M. E. Lleonart, T. Tsusaka, K. Hori, I. Murakami, T. Izumi, A. Takaori-Kondo, M. Yokode, G. Peters, D. Beach, H. Kondoh. Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2. The Journal of Cell Biology, 2014; DOI: 10.1083/jcb.201306149

Cite This Page:

The Rockefeller University Press. "Suppressing tumors by pulling the plug on glycolysis." ScienceDaily. ScienceDaily, 24 February 2014. <www.sciencedaily.com/releases/2014/02/140224123634.htm>.
The Rockefeller University Press. (2014, February 24). Suppressing tumors by pulling the plug on glycolysis. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2014/02/140224123634.htm
The Rockefeller University Press. "Suppressing tumors by pulling the plug on glycolysis." ScienceDaily. www.sciencedaily.com/releases/2014/02/140224123634.htm (accessed October 23, 2014).

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