Chemotherapy and radiation have long been among the most powerful clinical weapons available to fight cancer, despite their toxicity. These therapies were originally developed empirically, however, and it is only in recent years that scientists have begun to work out precisely how they are able to counter cancerous-cell growth, opening the possibility of rational improvements.
In a significant advance toward understanding the underlying mechanisms responsible for the effectiveness of these treatments, investigators at the University of Pennsylvania Medical Center and the Howard Hughes Medical Institute (HHMI) now report identification of a new so-called death-receptor gene called KILLER/DR5 that responds to chemotherapy and radiation by killing cancer cells. The team's findings, detailing a series of molecular events in a pathway that leads to cancer-cell death, appear in the October issue of Nature Genetics.
"Discovery of the KILLER/DR5 gene gives us new insight into how cancer cells treated with chemotherapy and radiation die," says senior author Wafik S. El-Deiry, MD, PhD, an assistant professor of medicine and genetics at Penn and an assistant investigator with HHMI.
The researchers found that when extra copies of the KILLER/DR5 were introduced into colon and liver cancer cells in laboratory experiments, cell growth was completely stopped.
"These findings suggest that substitution or reactivation of KILLER/DR5 in cancer cells may be a reasonable strategy for killing those cells," El-Deiry notes.
The cellular processes invoked by chemotherapy and radiation are complex and indirect, but powerful. Both therapies create breaks in the DNA of fast-dividing cells such as those of cancer, and this type of damage keys a gene called p53 to launch events on one of two molecular pathways. The first pathway leads to arrest of the cell-cycle and replication, and the other leads to apoptosis, or cell death. Either way, damaged cells are culled from the body and cancer growth is limited or stopped.
When p53 itself is damaged, however -- as is the case in many forms of cancer -- these protective pathways are disrupted. Loss of the p53-dependent apoptosis pathway, in particular, is thought to contribute strongly to cancer progression.
KILLER/DR5 represents a critical step in the apoptosis pathway. The new gene, inducible by DNA damage and regulated by p53, codes for what is known as a death receptor, the fifth such receptor so far identified. It is also a member of the tumor necrosis factor (TNF) receptor family. The receptor molecule has three parts: an extracellular region able to receive chemical instructions, a section that spans the cell membrane, and a cell-interior portion that contains a critical segment known as the death domain. When the extracellular region is activated, it triggers the death domain to initiate internal events leading to cell death.
"We have identified a gene that may play an important role in the success or failure of chemotherapy and radiation treatments for cancer," El-Deiry notes. "But our findings also tell us that the pathway of cell death involving these death receptors can be induced by DNA damage and is regulated by the tumor suppressor p53 -- information that was not previously known."
Additionally, KILLER/DR5 is located on the short arm of chromosome 8 in a region where sequence losses and translocations have been linked to many types of cancers. Because of its potent ability to kill cancer, KILLER/DR5 may be an entirely novel tumor suppressor gene.
"We are now very interested in identifying abnormalities in this pathway that may lead to cancer predisposition, as well as to the development of resistance to chemotherapy and radiation treatment," El-Deiry says.
The lead author on the Nature Genetics study is Gen Sheng Wu, MD, PhD. Additional Penn-based coauthors are Timothy F. Burns, BS; E. Robert McDonald III, BS; Wen Jiang, MD; Ray Meng, BS; Gary Kao, MD; Dai-Di Gan, MS; Ruth Muschel, MD, PhD; and Gary Wu, MD. Coauthor Nancy B. Spinner, PhD, an assistant professor of genetics at Penn, also has an appointment at the Children's Hospital of Philadelphia (CHOP). Ian D. Krantz, MD, and Jun-Ying Zhou, MD, are based at CHOP. Stanley R. Hamilton, MD, is at The Johns Hopkins University, and Sanford Markowitz, MD, PhD, is at Case Western Reserve University.
This work was supported by the University of Pennsylvania Cancer Center, one of 27 comprehensive cancer centers nationwide, as designated by the National Cancer Institute.
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