Photo by Todd McNaught
Cancer biologists know that eternal youth comes with a hefty price tag: immortality is a hallmark of most cancer cells. The link between aging and cancer is now clearer thanks to a new study that connects a powerful cancer-causing protein to a gene associated with Werner syndrome, a disease that causes premature aging.
A study led by Dr. Carla Grandori, staff scientist in Dr. Denise Galloway's Human Biology Division lab, finds that the cancer-promoting activity of Myc-a protein implicated in breast, prostate and many other tumors-depends in part on its ability to activate the WRN gene, whose absence leads to Werner syndrome.
The results of the study, which appears in the July issue of Genes and Development, leads researchers to speculate that a novel class of anti-cancer therapies might be developed based on drugs that interfere with the anti-aging properties of the WRN gene.
A tumor trigger
Werner syndrome is a rare genetic disorder that develops when the WRN gene is missing or defective. The disease causes the onset of premature aging shortly after puberty and results in the appearance of old age when patients are 30 to 40 years of age. Patients often die by age 50.
The syndrome is thought to occur because mutations in WRN cause genetic instability, a condition in which chromosomes are dramatically rearranged. Because genetic instability is also a common feature of tumor cells, Werner patients often die prematurely of cancers.
But the cancers that result from loss of the WRN gene differ from the tumors triggered by the Myc protein, which require an intact WRN gene, said Grandori, who was until May a staff scientist in Dr. Bob Eisenman's Basic Sciences Division laboratory.
Myc and immortality
"No one had implicated the Werner syndrome gene as a general pro-tumor agent," she said. "Patients with Werner's do develop cancers, but they are very rare cancers and tend to occur later in a patient's life. They don't develop Myc-related cancers, and our findings help to explain why."
Grandori said that Myc had already been known to cause cell immortality, a characteristic that enables tumors to grow indefinitely. She and colleague Dr. Riccardo Dalla-Favera of Columbia University, who is also a collaborator in the current study, discovered in 1999 that Myc switches on telomerase, an enzyme that extends the lifespan of cells.
Werner syndrome gene
"Although telomerase is important for immortalizing cells, it's not sufficient for all cell types," she said. "We asked, 'what other gene could be important for preventing senescence (aging)'? The Werner syndrome gene was an obvious candidate."
Using human cells grown in the laboratory, Grandori found that when Myc was overproduced, activity of the Werner syndrome gene was similarly induced and cells became immortalized. In cells in which the Werner syndrome gene was missing, an overabundance of Myc caused the cells to rapidly age. Aging cells have a flat appearance, stop dividing and have a unique pattern of gene expression.
Grandori said the these results suggest that it may be possible to block Myc's tumor-promoting activity by inhibiting the WRN gene, which would cause the cells to begin the aging process and cease to grow. She speculates that such drugs would be unlikely to mimic the symptoms of Werner syndrome.
"If cancer cells have higher levels of WRN than normal cells, tumor cells are likely to be more susceptible than healthy cells to drugs that inhibit WRN, so that normal cells would be relatively unaffected by the treatment." she said. "This could be a new approach for treating many cancers, since Myc is associated with numerous tumor types."
Co-authors on the study included Celine Ngouenet, research technician in the Eisenman lab; Drs. Jonathan Grim and Bruce Clurman, Human Biology and Clinical Research divisions; Dr. Ray Monnat, University of Washington Departments of Pathology and Genome Sciences; and colleagues at Columbia University. Dr. Jeff Delrow, staff scientist and manager of the DNA array facility, contributed to the experimental analysis.