CK2 protein sustains colon cancer cells by sabotaging ability to commit suicide

February 23, 2005

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).
-end-
This work was supported in part by National Institutes of Health, a Cancer Center Support (CORE) grant and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.

St. Jude Children's Research Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.