New Chemotherapeutic Approach Will Selectively Starve Cancer Cells

Blocking the activity of the enzyme eukaryotic elongation factor 2 kinase (eEF2K), which is found in cancer cells but not in normal cells, prevents tumors from adapting to nutrient deprivation and may represent a new chemotherapeutic approach.

The eEF2K enzyme is an essential factor for protein synthesis. It promotes the GTP-dependent translocation of the growing protein chain from the A-site to the P-site of the ribosome. This protein is completely inactivated by EF2 kinase phosphorylation.

EEF2K, which is activated by AMP-kinase (AMPK), has been shown to confer cell survival under acute nutrient depletion by blocking translation elongation. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta cells.

Investigators at the University of Southampton (United Kingdom) reported in the May 23, 2013, issue of the journal Cell that tumor cells exploit the AMPK-eEF2K pathway to adapt to nutrient deprivation. Adaptation of cancer cells to nutrient withdrawal was found to be severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of eEF2K strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme.

Contributing author Dr. Christopher G. Proud, professor of biological sciences at the University of Southampton said, "Cancer cells grow and divide much more rapidly than normal cells, meaning they have a much higher demand for and are often starved of, nutrients and oxygen. We have discovered that a cellular component, eEF2K, plays a critical role in allowing cancer cells to survive nutrient starvation, whilst normal, healthy cells do not usually require eEF2K in order to survive. Therefore, by blocking the function of eEF2K, we should be able to kill cancer cells, without harming normal, healthy cells in the process."

"Protein synthesis – the creation of proteins within cells –is a fundamental process that enables cells to grow, divide, and function," said Dr. Proud. "If it goes wrong, it can contribute to the development of cancer. We are interested in how defects in this process can cause cancers and other diseases."

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