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.