Study of possible anticancer drug reveals new mechanism of gene regulation

Researchers at Washington University School of Medicine in St. Louis have discovered a possible new mechanism for regulating large groups of genes. While conducting yeast research on a potential new anticancer drug, the team identified a mechanism that enables the genome to silence large numbers of genes simultaneously, rather than each gene individually.

The finding emerged during research studying the molecular action of the drug rapamycin. Rapamycin currently is used to suppress the immune system following kidney transplantation, but it also is being investigated as a promising anticancer drug. Rapamycin stops tumor-cell growth through a mechanism unlike those used by other anticancer drugs. The findings are published in the December issue of Molecular Cell.

“This study shows how basic research can have a clinical impact,” says study leader X. F. Steven Zheng, Ph.D., assistant professor of pathology and immunology. “It gives us insights into the molecular mechanism of rapamycin’s antitumor activity and may provide new targets for drug development.”

As an immunosuppressant, rapamycin is different from other drugs. While other immunosuppressants tend to promote the growth of cancer cells, rapamycin blocks the proliferation of tumors. In addition, rapamycin blocks the development of blood vessels in tumors, a process known as angiogenesis. These features led doctors to test its use as an anticancer drug.

“For a single drug to block both tumor proliferation and angiogenesis is unique,” says Zheng, who is an investigator with the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Test-tube experiments done by others showed that rapamycin binds to a large, previously unknown cell protein known as target of rapamycin (TOR). TOR is found in organisms from yeast to humans, suggesting that it may serve an essential purpose in cells.

Zheng and colleagues used rapamycin to inactivate TOR, enabling them to examine both TOR’s function in the cell and how rapamycin works.

The researchers identified about 300 yeast genes involved in TOR-related activities. The product of one of these genes, a protein known as silent information regulator 3 (Sir3), normally clings to a battery of genes responsible for a stress protein, thereby keeping the genes inactive and silent. Stress proteins are molecules produced by cells during adverse growing conditions.

But the researchers found that when rapamycin inactivates TOR, Sir3 molecules detach from the line of stress-protein genes, triggering a stress response: The cells begin producing stress proteins, their walls thicken and they stop proliferating.

“This surprised us,” Zheng says. “TOR was not known to be directly involved in stress control. Also, this means of silencing many genes simultaneously suggests a new type of gene regulation.” Usually, genes are turned on or off individually by proteins targeted to specific genes, he says.

Furthermore, the investigators found that when rapamycin inactivates TOR, it also shuts down nutrient processing pathways, preventing yeast cells from using glucose to produce energy and amino acids to make new proteins.

Overall, the researchers conclude that when rapamycin inhibits TOR, it triggers a variety of responses, including stress and starvation responses. Together, these actions probably cause the cells to stop proliferating.

These insights into rapamycin’s action must now be verified in human cells.

Ai W, Bertram PG, Tsang CK, Chan T-F, Zheng XFS. Regulation of subtelomeric silencing during stress response. Molecular Cell, December 2002.

Funding from the National Institutes of Health supported this research.