New Strategy Shuts Down Protein Linked to Immune-System Cancers
UW Carbone Cancer Center - For Patients
Madison, Wisconsin - Researchers at the University of Wisconsin School of Medicine and Public Health and the BloodCenter of Wisconsin have developed a new strategy to shut down a key protein linked to both normal cell processes and, when uncontrolled, many kinds of cancer.
Surprisingly, the animal studies also showed that the strategy, which keeps the gene-regulating protein NF-κB from leaving the cell nucleus, is necessary for the formation of healthy B cells, critical players in the immune system.
The findings suggest that the strategy could be used to stop the NF-κB abnormalities that are known to cause B-cell cancers such as lymphomas and myelomas.
"We are now doing pre-clinical experiments to see if we can stop or slow tumor growth in B cells," says senior author Dr. Shigeki Miyamoto, professor at the McArdle Laboratory for Cancer Research at the School of Medicine and Public Health (SMPH) and a member of the UW Carbone Cancer Center.
Most gene regulators live and work inside the cell nucleus, but NF-κB is usually kept inactive in the cytoplasm, the part of the cell surrounding the nucleus. NF-κB becomes active when signals in at least two major pathways in the cytoplasm tell it to migrate rapidly to the nucleus and then back. When genetic mutations produce too many signals, or erratic ones, cancer can result.
In earlier experiments, Miyamoto's team found that one way NF-κB is kept latent in the cytoplasm is by the constant action of an inhibitor protein. In the current study, the scientists wanted to see what effect the inhibitor protein might have on laboratory animals.
Associate scientist Shelly Wuerzberger-Davis helped create a transgenic mouse in which portions of the location-controlling inhibitor protein were destroyed. This allowed inactive NF-κB to leave the cytoplasm and enter the nucleus with the inhibitor protein, where it was trapped and resisted activation.
The scientists thought the mice would die, because NF-κB deficiency is usually lethal. But the animals were not affected in many ways. Upon close inspection, B-cell expert and co-senior-author Dr. Demin Wang of the BloodCenter of Wisconsin Blood Research Institute found effects of the altered inhibitor protein specifically in B cells. The immune cells did not mature, antibodies were not produced, and lymph organs and tissues formed abnormally.
"Our initial findings through this collaboration are very significant," says Wang, a faculty member at the Medical College of Wisconsin. "They demonstrate that this novel regulation of the NF-κB family of molecules has biological function and that it is specific for B cells."
The B-cell connection quickly led the scientists to think about related cancers, says co-author Dr. David Yang, an SMPH assistant professor of pathology.
"In patients with multiple myelomas and mantle cell lymphomas, cancer cells often contain mutations that cause uncontrolled NF-κB activity to increase cancer cell survival and drug resistance," says Yang. Stopping the uncontrolled activity by keeping NF-κB in the nucleus could greatly improve the situation.
The researchers found that their manipulations affected signaling mechanisms in the two major pathways in the cytoplasm - the classical and the alternative.
"We believe we can hit the spot where all the pathways converge into the one mechanism that activates NF-κB," says Miyamoto. "I think this could have a considerable impact on malignancies related to NF-κB."
Date Published: 02/18/2011