Turn Off: Pathway Activation Discovery Could Lead to New Cancer Drugs

A discovery by University of Alabama at Birmingham researchers about a how a common cell pathway that helps regulate cell survival and production is turned on could lead to new treatments for autoimmune diseases and cancer.

The study, published in the July 2011 issue of the journal Blood, details for the first time how the JAK-STAT pathway is activated by the protein CK2. This is important because both the pathway and protein have been previously identified as being overactive in cancer and autoimmune diseases, said the study’s senior author Etty (Tika) Benveniste, Ph.D., professor and chair of the UAB Department of Cell Biology and associate director for basic science in the UAB Comprehensive Cancer Center.

“There should be a time-limited response from both of these that should be of benefit to the host, but something happens in cancer and autoimmune diseases and neither is turned off, helping diseased cells grow,” Benveniste said. “In discovering that the CK2 protein activates the JAK-STAT pathway, we can now look for ways to shut down both, which is important in cancer treatment, because if you shut down only one of these, cells can still grow. These findings will help enable the development of drugs to target blocking both the pathway and the protein, of which the ultimate goal is causing cell death in tumors.”

Benveniste and her colleagues looked at cells from patients with myleoproliferative disorders, which have been shown to have an overactive JAK-STAT pathway. Myeloproliferative disorders, which include chronic myelogenous leukemia, is the name for a group of conditions that cause blood cells – platelets, white blood cells and red blood cells – to grow abnormally in the bone marrow. Though myeloproliferative disorders are serious, and may pose certain health risks, people with these conditions often live for many years after diagnosis.

The research team, Benveniste said, wanted to know if the CK2 protein was involved in making the JAK-STAT pathway overactive because previous studies in their laboratory identified the tumor suppressor PML as a regulator of the JAK-STAT pathway, and PML is a building block of CK2.

“We wanted to know if there was a definitive link between the two because both CK2 and JAK-STAT signaling play pivotal roles in cell survival, proliferation and anti-death mechanisms, and their dysregulation are associated with cancer and other diseases,” Benveniste said. “However, little has been known about the potential communication between CK2 and the JAK-STAT pathway in cells.”

To test their theory about the link between the two, in a laboratory setting the researchers utilized small interfering RNA and pharmaceuticals designed to block CK2 expression or inhibit its activity and then examined the effects blocking it had on the activation of the JAK-STAT pathway. The results showed that JAK-STAT activation is dependent on the presence or activity of CK2.

“Through this study, we provided clear evidence that activation of the JAK-STAT signaling pathway is dependent on the presence and/or activity of CK2 in tumor cells,” Benveniste said. “There are a number of pharmaceutical companies that are generating inhibitors for both of these and some are in clinical trials now. Because of our observations, companies that produce these inhibitors can now test drugs that inhibit both on patients. Some of that is starting to happen now in people with myleoproliferative disorders, and future studies are planned on glioblastoma multiforme, the deadliest brain tumor, and breast cancer.”

Ying Zheng from UAB is the lead author on the study. Co-authors are Hongwei Qin, Stuart J. Frank, Luqin Deng, Fang-Tsyr Lin, Jingzhi Li and Bingdong Sha of UAB; David W. Litchfield, of the University of Western Ontario, London, Ontario, Canada; and Ayalew Tefferi and Animesh Pardanani, of the Mayo Clinic.

About the UAB Comprehensive Cancer Center
The UAB Comprehensive Cancer Center is among the 40 cancer centers in the nation to meet the stringent criteria for the National Cancer Institute’s comprehensive designation. The center is a leader in groundbreaking research, reducing cancer disparities and leading-edge patient care.

About UAB
Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is the state of Alabama’s largest employer and an internationally renowned research university and academic health center; its professional schools and specialty patient-care programs are consistently ranked among the nation’s top 50. Find more information at http://www.uab.edu and http://www.uabmedicine.org.

EDITOR’S NOTE: The University of Alabama at Birmingham (UAB) is a separate, independent institution from the University of Alabama, which is located in Tuscaloosa. Please use University of Alabama at Birmingham on first reference and UAB on all consecutive references.

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Source: University of Alabama at Birmingham