Researchers may have found out how cancer cells continuously activate a protein that keeps the disease growing and spreading. The finding, reported in the December 2010 issue of Nature Medicine, sheds light on a long-standing mystery and points to possible new anticancer drug targets.
|Heehyoung Lee, Ph.D., found a feedback loop behind a cancer-boosting protein’s activation. (Photo by Darrin S. Joy)|
When activated, a protein called signal transducer and activator of transcription-3, or STAT3, protects tumor cells from the body’s immune system and also pushes cancer to grow and spread. It is highly activated in tumor cells.
Before the current study, scientists were not clear on the process that drove cancer cells to continuously activate STAT3. Now, a City of Hope team has discovered that a molecular feedback loop may be responsible. Hua Yu, Ph.D., professor, and Heehyoung Lee, Ph.D., assistant research professor, both in the Department of Cancer Immunotherapeutics and Tumor Immunology, led the research.
In normal cells, STAT3 activation is linked to two proteins, interleukin-6 (IL-6) and Janus kinase (JAK). These two proteins are part of a cascade of activity that eventually activates STAT3. However, IL-6-JAK activation of STAT3 is only temporary in normal cells, so researchers wanted to know what is different in tumor cells to keep STAT3 activated.
Their first clue came from a protein called sphingosine-1-phosphate receptor-1, or S1PR1. They found higher levels of S1PR1 in tumors, which meant the gene that produces S1PR1 was more active.
STAT3 is linked to the S1PR1 gene in two ways: STAT3 promotes the gene’s activity, and the gene returns the favor by activating STAT3. This also leads to higher IL-6 levels.
“This positive feedback loop is largely responsible for keeping STAT3 activated in tumor cells and other cells within the tumors,” said Yu. “And the increase in IL-6 also promotes tumor growth and metastasis.”
The team tested the link to the S1PR1 gene by cutting off the gene’s activity in mice. When they did, they found STAT3 activation dropped, and tumor growth and spread decreased.
“Aside from helping us understand what’s keeping STAT3 persistently activated, these results are exciting for the clues they give for possible new drug targets to block STAT3 activation,” said Lee, who is first author on the study.
The team now hopes to tease out what some of those new targets might be.
Other authors on the study include Jiehui Deng, Ph.D., Maciej Kujawski, Ph.D., Chunmei Yang, Ph.D., Yong Liu, Ph.D., Andreas Herrmann, Ph.D., Marcin Kortylewski, Ph.D., David Horne, Ph.D., George Somlo, M.D., Stephen J. Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Richard Jove, Ph.D., Morgan and Helen Chu Director’s Chair of Beckman Research Institute. The study was supported by grants from the National Institutes of Health and the National Cancer Institute and by American BioScience.