Investigator: Achim Temme
by Julie Clayton
Avoiding death is the hallmark of cancer cells, and one newly discovered strategy is to send into 'exile' a protein that would otherwise render the cells prone to suicide, or apoptosis.
The finding could open a new avenue for developing future therapies that boost the sensitivity of cancer cells to apoptosis-inducing drugs by blocking the exile process, says Achim Temme, group leader at the Institute of Immunology, of the Technical University of Dresden.
The exiled protein is survivin - until now known only for its association with tumor cells. Tumors can be divided according to their aggressiveness, depending on the location of survivin in the cell, according to previous work by other groups.
Tumor samples from patients who responded poorly to treatment are more likely to have survivin concentrated in the cytosol, while tumor cells from patients with a good prognosis tend to have survivin localized to the nucleus.
These studies led to the notion that tumors could become more aggressive if survivin shuttled out of the nucleus and into the cytosol, where its presence somehow blocked a biochemical pathway leading to apoptosis - the more survivin in the cytosol, the greater the escape from suicide.
Temme and his team were intrigued to find out whether survivin might perform a similar task in normal cells, and produced an unexpected result.
Using normal human fibroblasts derived from lung tissue, they tagged the survivin protein with the fluorescent protein GFP, and used sensitive microscopy to show that the protein occurs preferentially in the nucleus, but there appeared to be some shuttling of survivin out of the nucleus.
The cells were sensitive to C2 ceramide, an agent commonly used to trigger apoptosis experimentally. However, leptomycin B, which blocks a mechanism that exports proteins from the nucleus, causes survivin to accumulate in the nucleus, and boosts the cells' susceptibility to apoptosis.
Extrapolating to the previous studies on cancer cells, Temme suggests that rather than enhancing cancer cell survival through blocking a suicide pathway, the presence of survivin in the cytosol could instead reflect a different strategy of removing survivin from the nucleus where it would otherwise assist with suicide.
"The location is important to whether it is anti-apoptotic or pro-apoptotic," he said. "In the cancer cell, you have the increase in the export of survivin out of the nucleus, and therefore a rescue from apoptosis, and not the other way round."
The researchers are now looking to identify the mechanism by which survivin enhances apoptosis in normal cells, and suspect that it could involve an increase in the expression of the BCL and Vax genes known to be involved in apoptosis.
Ultimately, the work might encourage the development of drugs that in patients could achieve a similar block in the nuclear export of survivin in cancer cells, leading to greater sensitivity to apoptosis-triggering drugs. "We'll have to look for that as a strategy," said Temme.
