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 How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>