By amplifying cell death signals, scientists make precancerous cells self-destruct

August 15, 2008

When a cell begins to multiply in a dangerously abnormal way, a series of death signals trigger it to self-destruct before it turns cancerous. Now, in research to appear in the August 15 issue of Genes & Development, Rockefeller University scientists have figured out a way in mice to amplify the signals that tell these precancerous cells to die. The trick: Inactivating a protein that normally helps cells to avoid self-destruction.

The work, led by Hermann Steller, Strang Professor and head of the Laboratory of Apoptosis and Cancer Biology, is the first to reveal the mechanism by which a class of proteins called IAPs regulates cell death. By exposing the mechanism in a living animal, the finding also marks a breakthrough in the field and opens the door for developing a new class of drugs that could aid in cancer therapy and prevention.

"In a way, these mice are guiding clinical trials," says Steller, who is also a Howard Hughes Medical Institute investigator. "We now can study how IAPs contribute to the development of cancer in a living animal and develop drugs to prevent or thwart the disease."

IAP stands for "inhibitor of apoptosis protein," and these proteins do exactly what their name implies. By inhibiting apoptosis, or programmed cell death, they keep cells alive by directly binding to executioner enzymes called caspases. But until now, precisely how IAPs save cells from death has remained unclear.

With graduate student Andrew Schile and postdoc Maria Garcia-Fernandez, Steller studied the X-linked inhibitor of apoptosis protein, or XIAP, and the role of its largely ignored RING domain, which has been implicated in promoting cell death as well as survival. Steller, Schile and Garcia-Fernandez found that genetically targeting and removing RING affected only some cell types in healthy mice. And even though the mice without the RING had more cell death than the mice with the RING, both lived normal lives under normal laboratory conditions.

But when the scientists compared mice that were genetically predisposed to developing cancer, they found that those without the RING lived twice as long as those with it.

"Cancer cells thrive by disabling the molecular machinery that tells sick cells to die," says Steller. "By removing the RING, we wanted to see whether we would trick the machinery to turn back on. And that's what happened. Cells die more readily, making it much more difficult for cancer to be established."

Steller and his team specifically showed that the RING transfers molecular tags on caspases that label these enzymes for destruction. The more tags, the stronger the signal to save the cell from death. However, when the RING is removed, fewer molecular tags are transferred to caspases and often, the signal to save the cell from death is not strong enough. So, more cells die.

The game is not over. Several distinct IAP genes are known to exist, but which ones are important in the development of cancer has also stymied researchers. "We need to use genetics to sort out which individual IAPs contribute to tumors and which IAPS we need to target in order to cure cancer," says Steller. "This was a very big step in understanding what role IAPs play in cancer, but it isn't the last."

Source: Rockefeller University

Explore further: New study offers novel treatment strategy for patients with colon cancer

Related Stories

New study offers novel treatment strategy for patients with colon cancer

September 20, 2017
Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide.

New clinical trial explores combining immunotherapy and radiation for sarcoma patients

September 20, 2017
University of Maryland School of Medicine researchers are investigating a new approach to treat high-risk soft-tissue sarcomas by combining two immunotherapy drugs with radiation therapy to stimulate the immune system to ...

Finding a natural defense against clogged arteries

September 20, 2017
In type 2 diabetes, chronic inflammation drives cardiovascular disease, the leading cause of death among people with the condition. Researchers at Joslin Diabetes Center now have identified an unexpected natural protective ...

Newly ID'd role of major Alzheimer's gene suggests possible therapeutic target

September 20, 2017
Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer's disease—one that increases a person's chances of developing the neurodegenerative disease by up to 12 ...

Laser device placed on the heart identifies insufficient oxygenation better than other measures

September 20, 2017
A new device can assess in real time whether the body's tissues are receiving enough oxygen and, placed on the heart, can predict cardiac arrest in critically ill heart patients, report researchers at Boston Children's Hospital ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Recommended for you

Researchers develop treatment to reduce rate of cleft palate relapse complication

September 22, 2017
Young people with cleft palate may one day face fewer painful surgeries and spend less time undergoing uncomfortable orthodontic treatments thanks to a new therapy developed by researchers from the UCLA School of Dentistry. ...

Exosomes are the missing link to insulin resistance in diabetes

September 21, 2017
Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now.

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

As men's weight rises, sperm health may fall

September 20, 2017
(HealthDay)—A widening waistline may make for shrinking numbers of sperm, new research suggests.

Researchers find way to convert bad body fat into good fat

September 19, 2017
There's good fat and bad fat in our bodies. The good fat helps burn calories, while the bad fat hoards calories, contributing to weight gain and obesity. Now, new research at Washington University School of Medicine in St. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.