Novel Death-Receptor Gene Identified: KILLER/DR5 Triggers Cancer Cell Death After Chemotherapy Or Radiation

September 29, 1997

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.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page ( and to EurekAlert! (, an Internet resource sponsored by the American Association for the Advancement of Science.

University of Pennsylvania School of Medicine

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 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