Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find molecular 'brake' to cell death

03.07.2006
Researchers at The University of Texas M. D. Anderson Cancer Center have significantly refined the scientific understanding of how a cell begins the process of self-destruction - an advance they say may help in the design of more targeted cancer therapies.

In the June 30 issue of the journal Cell, the research team found that a natural "brake" exists in a cell to prevent it from undergoing apoptosis, or programmed cell death, and they say that optimal anti-cancer therapies should take a two-pronged approach to overriding this brake in order to force a tumor cell to die. Very few drugs do this now, they say.

The discovery "demonstrates that apoptosis is more complicated than had been believed, and consequently harder to achieve," says the study's lead author, Dean G. Tang, Ph.D., associate professor in the Department of Carcinogenesis in the Science Park Research Division of M. D. Anderson in Smithville, Texas.

Apoptosis can occur when a cell has reached its lifespan, and so is "programmed" to die, or is initiated when a cell is damaged beyond repair or infected by a virus. Apoptosis is rare in cancer because tumor cells have adapted biological pathways to circumvent cell death, so many anti-cancer therapies focus on inducing apoptosis in these cells, Tang says.

But the notion of how to push cancer cells to die has been flawed, Tang says. These new findings "overturn a scientific dogma so long accepted that it has become a textbook standard when talking about apoptosis," he continues.

Researchers agree that the seminal event that leads to initiation of apoptosis is the release of a key protein known as cytochrome c (CC) from a cell's mitochondria, the organelle's energy storehouse. These molecules then bind to another protein called Apaf-1 in the cell cytoplasm, and together they form a scaffolding "death wheel" to activate enzymes called caspases that shred a cell apart.

But what they also believed is that a cell needs extra energy from ATP to undergo apoptosis, and that this extra energy was produced from the "pools" of free nucleotides that exist in the cell cytoplasm. Nucleotides are the primary structural chemical units that make up DNA, RNA and proteins, and they combine to play a variety of roles in the cell, such as formation of ATP.

However, through a series of biological and biochemical experiments, Tang and his research team found that adding ATP to a cancer cell could potentially impede apoptosis. They discovered that these nucleotide pools, in fact, act not to promote apoptosis through production of ATP, but to hinder it. They are "pro-survival factors" that prevent CC, when released from the mitochondria, from "seeing" Apaf-1 in the cytoplasm, Tang says.

"When we induced some cell stress and damage, the low levels of CC that came out from the mitochondria were ineffective because they are sequestered by an ocean of free nucleotides and ATP," he says. "No one had ever realized this kind of barrier existed to impede apoptosis."

They found that cell mitochondria needed to release a large and sustained volume of CC to overcome this nucleotide barrier, and they also found evidence that as soon as the release of CC increases, another mechanism kicks in that simultaneously begins to reduce the size of the nucleotide pool to allow CC to bind to Apaf-1, Tang says.

The researchers say this kind of strategy makes sense for the cell, because it acts like a biological fail-safe system to protect against the errant release of CC from malfunctioning mitochondria. A large pool of free nucleotides along with complete ATP molecules normally exists in a healthy cell so that just a little CC could not mistakenly push the cell to self destruct, Tang says. "When CC is still limited in the cell, perhaps through an accidental release, the nucleotide pool will neutralize the CC so that the cell can stay alive," he says. "So, in a way, it takes a large amount of CC to convince the cell that the damage is real, and that is what you see when cardiac cells die after a heart attack, for example."

This finding has direct implications for anti-cancer therapy, Tang says, suggesting how current therapy could be both inefficient and lead to resistance in a cell.

"Many cancer drugs focus on pushing the mitochondria to release CC, and not on reducing the nucleotide pool, and our new model suggests that decreasing this pool is essential to produce sensitivity in cancer cells to apoptosis," Tang says.

Cancers that quickly become resistant to therapy, such as melanoma and ovarian tumors, do so because they have found ways to prevent mitochondria from releasing a lot of CC, he says. Tumor cells also don't want to decrease their nucleotide pool, because they need ATP for continued functioning, he says.

"An optimal cancer therapy should combine both strategies," Tang says. "They should maximize release of CC and maximize the decrease of nucleotide levels."

Some chemotherapy drugs, like paclitaxel, cisplatin and etoposide, appear, coincidentally and perhaps inadvertently, to do both, and are very effective for specific cancers, he says. "But based on these new findings, we now have a new theoretical approach that can be used to help in the design of more targeted chemotherapy drugs," Tang says. "This will change the way that scientists now think about the role of nucleotides in cancer therapy."

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Life Sciences:

nachricht High-Speed Locomotion Neurons Found in the Brainstem
24.10.2017 | Universität Basel

nachricht Antibiotic resistance: a strain of multidrug-resistant Escherichia coli is on the rise
24.10.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Single nanoparticle mapping paves the way for better nanotechnology

24.10.2017 | Physics and Astronomy

A quantum spin liquid

24.10.2017 | Physics and Astronomy

Antibiotic resistance: a strain of multidrug-resistant Escherichia coli is on the rise

24.10.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>