A protein called CK2 plays a deadly role in colorectal carcinoma by blocking the ability of these tumors to activate a natural self-destruct mechanism that would clear this cancer from the body. This finding, by researchers at St. Jude Children's Research Hospital, is currently published in the online edition of Oncogene.
The renegade CK2 protein keeps the tumor alive and growing by desensitizing the cancer cells to the effects of another protein called TRAIL. Normally, TRAIL triggers apoptosis (cell suicide) in the cancer cells as a way of protecting the body. CK2 is an enzyme composed of four small proteins--two alpha proteins and two beta proteins.
The finding holds promise for developing drugs that help a patient's cancer cells become sensitized to TRAIL-induced apoptosis. For example, treating the tumors with TRAIL to trigger apoptosis while blocking CK2 might enhance anti-cancer treatment for a variety of other solid tumors, such as pediatric rhabdomyosarcoma, according to Janet Houghton, Ph.D., a member of St. Jude Hematology-Oncology. Rhabdomyosarcoma is a tumor originating in cells that have some features of muscle cells.
The St. Jude team showed that CK2 exerts its anti-apoptosis effect within a structure called DISC (death-inducing signaling complex). The DISC is a large jumble of proteins that interact with each other after TRAIL binds to the outer cell membrane. After DISC forms, an enzyme called caspase-8 triggers the cascade of biochemical events outside DISC that eventually leads to cell death. By desensitizing the cell to TRAIL, CK2 disrupts the DISC response, which in turn prevents apoptosis and allows the cancer cell to continue growing.
"The work my laboratory has done using our cell lines of colorectal cancer to investigate the role of CK2 in tumors is now bearing fruit," said Houghton, senior author of the Oncogene report. "We've shown in some detail how CK2 helps cancer cells survive the natural tendency for abnormal cells to self-destruct, as well as how to block CK2 and permit the cell to undergo apoptosis. In doing so, we've begun to map out a strategy for making cancer cells more likely to self-destruct."
The findings of the current study support and expand those published by Houghton's laboratory last October in the journal Clinical Cancer Research. In that study, the team reported similar findings in rhabdomyosarcoma cells.
In the current study using human colon carcinoma cells, the researchers found that while CK2 usually is continually active, they could block this activity using a CK2-inhibitor called DRB.
Subsequently, the team showed that blocking CK2 with DRB made the cells very sensitive to TRAIL, causing them to commit suicide. This proved the important role CK2 played in preventing TRAIL-induced cell suicide. However, DRB did not have an effect on normal cells, which strongly suggests that CK2 blocks apoptosis only in cancer cells.
Because DRB can also interfere with other cellular reactions, the researchers blocked CK2 using another technique: short hairpin RNA (sh RNA). This technique uses a tiny bit of genetic material specifically designed to shut down a particular gene--in this case, the gene for the alpha proteins that make up part of CK2. Again, CK2 activity was lost, the cancer cells were sensitized to TRAIL, and the cells committed suicide.
The researchers also showed that the ability of TRAIL to trigger apoptosis depended on caspase enzymes, such as caspase-8. Caspase enzymes are part of the biochemical pathway that triggers the cell to undergo apoptosis. Specifically, when the team added to the cancer cells a drug that blocks caspases, TRAIL-induced apoptosis was also blocked.
"Our discovery that blocking CK2 makes cancer cells sensitive to TRAIL-induced cell suicide is very promising," said Kamel Izeradjene, Ph.D., a postdoctoral student in Houghton's lab who did much of the work reported in Oncogene. "We hope to find effective drugs that block CK2 in samples of tumors removed from children treated at St. Jude."
"This is a translational research laboratory," Houghton said. "Our aim is to translate discoveries made here into better treatments for children with solid tumors."
Houghton currently collaborates on colorectal cancer treatment studies with physicians at the West Clinic in Memphis and is also working with a commercial firm to develop treatments for solid tumors based on her St. Jude work.
Other authors of the article are Leslie Douglas and Addison Delaney (St. Jude).