Suicidal cancer cells sustained by protein

The findings are important as they pave the pathway to finding effective drugs that block CK2 and developing treatments for a cancer that affects nearly 160,000 Americans and the 20,000 new victims per year in the UK.

The team, from St. Jude Children's Research Hospital​, showed that CK2 exerts its anti-apoptosis effect within a structure called DISC (death-inducing signalling 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 leading to cell death. By desensitising the cell to TRAIL, CK2 disrupts the DISC response, which in turn prevents apoptosis and allows the cancer cell to continue growing.

"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,​ said Janet Houghton, a member of St. Jude Haematology-Oncology.

"In doing so, we've begun to map out a strategy for making cancer cells more likely to self-destruct."​

Scientists found that the CK2 protein keeps the tumour alive and growing by desensitising 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.

The findings holds promise for developing drugs that help a patient's cancer cells become sensitised to TRAIL-induced apoptosis. Treating the tumours with TRAIL to trigger apoptosis while blocking CK2 might enhance anti-cancer treatment for a variety of other solid tumours, such as paediatric rhabdomyosarcoma.

The current study used human colon carcinoma cells. The researchers found that while CK2 usually is continually active, using a CK2-inhibitor called DRB could block the protein.

The researcher's next step was to block CK2 with DRB making 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 also interferes 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 designed to shut down a particular gene. In this research, the gene for the alpha proteins that make up part of CK2 was targeted. They found that CK2 activity was lost, the cancer cells were sensitised to TRAIL, and the cells committed suicide.

The researchers also showed that the TRAIL's ability 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. 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, a postdoctoral student in Houghton's lab.

"We hope to find effective drugs that block CK2 in tumour samples."​

Intravenous 5-fluorouracil (5-FU) combined with leucovorin (LV) chemotherapy remains the standard of care for advanced colorectal cancer. Alternative treatments, such as oral fluoropyrimidine analogues, may replace 5-FU/LV in the future, as may other combination regimens currently under investigation.

Novel treatment approaches using biological therapy are showing promising results, particularly cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody. To data, no phase 3 randomised data is yet available on these therapies.

This finding is currently published in the online edition of Oncogene.​