Sci. Aging Knowl. Environ., 25 February 2004
Vol. 2004, Issue 8, p. nf21
[DOI: 10.1126/sageke.2004.8.nf21]

NEWS FOCUS

Stop a Tumor, Save a Cell

Cancer fighter helps cells survive lean times

Mitch Leslie

http://sageke.sciencemag.org/cgi/content/full/2004/8/nf21

Tumor-suppressing proteins are supposed to be tough guys that execute faulty cells or squelch their reproduction. But according to a new study, one such protein nurtures some types of cells, fostering their recovery from starvation. The results bolster a recently discovered metabolic link between diabetes and cancer and could help researchers design new drugs to battle the diseases.

A cell that's low on energy must economize or perish. The cellular manager AMP-activated protein kinase (AMPK) senses low energy supplies and triggers ATP-producing biochemical pathways. It also slows or stops cell activities that deplete energy. AMPK goads cells to absorb glucose, and researchers are investigating whether hiking its activity level when sugar concentrations aren't low might help ameliorate diabetes. Last fall, studies by two groups nabbed a protein that directly turns on AMPK in cells: a tumor-prevention protein called LKB1. Researchers had connected LKB1 to cancer--a faulty version of its gene underlies many lung tumors and a rare disease in which patients develop gastrointestinal polyps--but nobody suspected that the protein meddles with metabolism. Shaw and colleagues wanted to find out how LKB1 helps cells cope with energy shortages.

Starving cells often commit suicide, but AMPK keeps them alive. Because LKB1 activates AMPK, the researchers tested whether LKB1 underlies this protection. They doused cells from mouse embryos and from human cervical tissue with a compound that mimics AMP, an indicator of low energy supplies. Cells engineered to lack LKB1 were more than four times as likely to kill themselves as were cells with the protein. The findings suggest that when a cell's gas tank nears empty--indicated by abundant AMP--LKB1 rouses AMPK and stays cellular suicide. Prodding LKB1 might provide a way to crank up AMPK and hamper diabetes, the researchers conclude.

Paradoxically, lack of LKB1 seems to promote tumor growth but also drive cell suicide. The outcome depends on whether the cell is under stress, according to the researchers' model. Even well-fed cells probably carry some activated AMPK, says co-author Lee Witters, a biochemist at Dartmouth College in Hanover, New Hampshire. By limiting metabolic processes necessary for growth, such as protein synthesis, it 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. But if the cell is under stress from, say, food scarcity, the situation changes. A cell with LKB1 can boost AMPK activation and restore its energy supply. LKB1 buys time for famished cells to recover, says Witters. But if the cell lacks LKB1, it can't implement these emergency energy-saving measures and kills itself.

"It's good work" that strengthens the connection between metabolism and unfettered cell division, says cell biologist Morris Birnbaum of the University of Pennsylvania in Philadelphia. However, biochemist David Carling of the MRC Clinical Sciences Centre in London wants to see stronger evidence that LKB1 shields energy-deprived cells. Carling, who co-authored one of the previous papers that fingered LKB1, notes that the AMP-mimicking compound the researchers used can spur cell death without affecting the AMPK pathway. But the findings bolster existing evidence that AMPK plays a role in cancer and diabetes, he says. The discovery will encourage researchers to coax out LKB1's softer side.


February 25, 2004
  1. R. J. Shaw et al., The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. U.S.A., week of 23 February 2004 [e-pub ahead of print]. [Abstract] [Full Text] [Links will work when the article goes online.]
Citation: M. Leslie, Stop a Tumor, Save a Cell. Sci. Aging Knowl. Environ. 2004 (8), nf21 (2004).








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