How cancer cells rewire their metabolism to survive

By Heather Buschman, Ph.D.
January 31, 2013
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Researchers discover that tumors lacking the protein PKCζ are good at surviving when nutrients are scarce—opening a new therapeutic avenue that targets cancer metabolism.

Cancer cells need food to survive and grow. They’re very good at getting it, too, even when nutrients are scarce. Many scientists have tried killing cancer cells by taking away their favorite food, a sugar called glucose. Unfortunately, this treatment approach not only fails to work, it backfires—glucose-starved tumors actually get more aggressive. In a study published January 31 in the journal Cell, researchers discovered that a protein called PKCζ is responsible for this paradox. The research suggests that glucose depletion therapies might work against tumors as long as the cancer cells are producing PKCζ.

PKCζ: critical regulator of tumor metabolism

According to this study, when PKCζ is missing from cancer cells, tumors are able to use alternative nutrients. What’s more, the lower the PKCζ levels, the more aggressive the tumor.

“We found an interesting correlation in colon cancers—if a patient’s tumor doesn’t produce PKCζ, he has a poorer prognosis than a similar patient with the protein. We looked specifically at colon cancer in this study, but it’s likely also true for other tumor types,” said Jorge Moscat, Ph.D., a professor at Sanford-Burnham. Moscat led the study in close collaboration with colleague Maria Diaz-Meco, Ph.D.

PKCζ keeps tumors addicted to glucose, and under control

Jorge Moscat and Maria Diaz-Meco

Although most cancer cells love glucose, tumors lacking PKCζ grow even better in the absence of this nutrient. Using human tumor samples and a mouse model of colon cancer, Moscat and his team determined this growth-without-glucose paradox is because PKCζ-deficient tumors are able to reprogram their metabolism to use glutamine, another nutrient, instead.

Without PKCζ around to keep them addicted to glucose, these tumors kick-start a new metabolic pathway. This altered metabolism helps PKCζ-deficient cancer cells survive in conditions that would otherwise be lethal.

“If we can find an effective way to add PKCζ back to tumors that lack it, we’d make them less suited for survival and more sensitive to current therapies,” Moscat said.

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This study was funded by the U.S. National Institutes of HealthNational Cancer Institute grants R01CA132847, R01CA134530, R21CA147978 and 5P30CA030199-31; National Institute of Allergy and Infectious Diseases grant R01AI072581; and National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK088107.

Original paper:

Ma L, Tao Y, Duran A, Llado V, Galvez A, Barger JF, Castilla EA, Chen J, Yajima T, Porollo A, Medvedovic M, Brill LM, Plas DR, Riedl SJ, Leitges M, Diaz-Meco MT, Richardson AD, & Moscat J (2013). Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis. Cell, 152 (3), 599-611 PMID: 23374352

ResearchBlogging.org

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About Author

Heather Buschman, Ph.D.

Heather was a Sanford-Burnham Communications staff member.

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1 Comment

  1. As cancer cells become more DEdifferentiated the penthose phosphate shunt becomes increasingly active, indicating that the cell is making its own DNA and RNA, an indication of autocrine stimulation or DIY.. What about a source of nitrogen for these nucleosides. Glutamine! However if the cell is no longer using glucose, no penthose sugars. This DIY cell also makes it’s own membrane fats from glucose, ignoring dietary fats, thus limiting it to oleic and saturated fats, no problem for membrane permeability as the cell runs HOTTER.

    Problem. As glutamine enters the TCA cycle as glutamate, there is no glycolytic or penthose shunt activity so I cannot see how the cell can possible function without glucose. Is there some mistake?

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