Navigation Links
Researchers Find Molecular "Brake" to Cell Death

Researchers 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.

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 t hat 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."

(Source: Newswise)

Related medicine news :

1. Researchers urge caution in using ear tube surgery
2. Researchers Scale to assess the Severity of Epilepsy in Kids
3. Researchers trick Alzheimers Enzyme
4. Researchers find new HIV hiding place
5. New Hair in 15 Days Could Now Be A Possibility Say Researchers
6. Researchers developed world’s smallest toothbrus
7. Researchers discover receptor cells that can cause epilepsy
8. 15 Anti-SARS Drugs Identified By China-Europe Team of Researchers
9. Researchers reversed the process of memory loss
10. Researchers Identify Key Gene That May Help Brain Treatment
11. Researchers Discover Protein That Causes Malaria
Post Your Comments:

(Date:6/24/2016)... ... ... June 19, 2016 is World Sickle Cell Observance Day. In an effort to ... treatments, Serenity Recovery Center of Marne, Michigan, has issued a pain management ... (SCD) is a disorder of the red blood cells, which can cause episodes of ...
(Date:6/24/2016)... ... 2016 , ... The Pulmonary Hypertension Association (PHA) learned during ... two significant new grants to support its work to advance research and patient ... recognizing patients, medical professionals and scientists for their work in fighting pulmonary hypertension ...
(Date:6/24/2016)... ... June 24, 2016 , ... ... for accelerated orthodontic treatment. Dr. Cheng has extensive experience with all areas of ... AcceleDent, and accelerated osteogenic orthodontics. , Micro-osteoperforation is a revolutionary adjunct to ...
(Date:6/24/2016)... , ... June 24, 2016 , ... Topical BioMedics, Inc, makers of Topricin and MyPainAway ... call for a minimum wage raise to $12 an hour by 2020 and then adjusting ... restore the lost value of the minimum wage, assure the wage floor does not erode ...
(Date:6/24/2016)... ... June 24, 2016 , ... ... the Clinical Decision Making in Emergency Medicine conference in Ponte Vedra Beach, FL. ... articles published in Emergency Medicine Practice and Pediatric Emergency Medicine Practice. ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... FRANCISCO, Calif. , June 24, 2016 /PRNewswire/ ... ), a biopharmaceutical company developing novel therapeutics for ... unmet needs, today announced the closing of its ... of common stock, at the public offering price ... in the offering were offered by GBT. GBT ...
(Date:6/24/2016)... Research and Markets has ... 2015-2025: Applications, Technologies, Forecasts" report to their ... Electronics, Smart Skin, Structural Health Monitoring, Composite Smart ... electronics involves electronic and/or electrical components and circuits ... structures such as vehicle bodies or conformally placed ...
(Date:6/24/2016)... , June 24, 2016  American Respiratory Labs (ARL), a ... now able to perform sophisticated lung assessments in patients, homes, thanks ... Inc. Patients are no longer limited to having ... PRO ® , ARL patients like Jeanne R. of ... the comfort of her own home. ...
Breaking Medicine Technology: