For Release: April 27, 2004
Contact: DMS Communications(603) 650-1492

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Protein May Thwart Tumors

HANOVER, NH--Recent research on the interaction of two protein kinases, one that acts as a cellular fuel gauge and the other that prevents tumors, boosts the link between metabolism and cell proliferation. The work offers a stepping stone to new strategies for drugs against diabetes and cancer.

Dr. Lee Witters, professor of medicine and of biochemistry, and of biological sciences in the college, with colleagues at Harvard, has found that the energy sensor AMP-activated kinase (AMPK) is turned on by the tumor suppressor LKB1 kinase when cells are stressed. Their study, published in the March 9 Proceedings of the National Academy of Sciences (PNAS), suggests an explanation for the paradox that lack of LBK1 seems to increase tumor growth yet also prompt cell death.

Kinases encompass a large family of proteins that play key roles in the workings of most animal cells. AMPK is a cellular manager that responds to insulin or glucose and mediates impaired energy metabolism, a defect in type 2 diabetes. Another kinase, LKB1, that appears to thwart tumors, also activates AMPK.

Testing cells under stress conditions in a mouse model, the researchers demonstrated how LBK1 protects low-energy cells by ramping up AMPK. As a conequence, the weak cells that might otherwise have died are saved.

"Even well-fed cells probably carry some activated AMPK. By limiting metabolic processes needed for growth, such as protein synthesis, AMPK prevents cells from multiplying rapidly, which hurts cancer cells disproportionately. Removing LKB1 eliminates AMPK activity and cancels this check on proliferation, allowing tumors to prosper," says Witters. "The situation changes under a stress such as food scarcity. A cell with LKB1 can boost AMPK activation and restore its energy supply. LKB1 buys time for famished cells to recover. But if the cell lacks LKB1, it can't implement these emergency energy-saving measures and kills itself." The findings offer a model for model for LKBI as a low-energy checkpoint tumor suppressor, conclude the authors, who also include Dartmouth graduate student Rebecca Hurley. Further insights into the ties among energy metabolism, cell growth and cell death can pave the way for therapy tailored to genetic defects in a pathway that affects fundamental processes.