Navigation Links
Researchers find molecular 'brake' to cell death

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."


'"/>

Source:University of Texas M. D. Anderson Cancer Center


Related biology news :

1. Researchers discover way to make cells in the eye sensitive to light
2. Researchers find how protein allows insects to detect and respond to pheromones
3. Researchers Uncover Key Step In Manufacture of Memory Protein
4. Researchers reveal the infectious impact of salmon farms on wild salmon
5. Researchers identify target for cancer drugs
6. Researchers discover molecule that causes secondary stroke
7. Researchers find missing genes of ancient organism
8. Researchers trace evolution to relatively simple genetic changes
9. Researchers add new tool to tumor-treatment arsenal
10. UF Researchers Map Bacterial Proteins That Cause Tooth Loss
11. VCU Researchers Identify Networks Of Genes Responding To Alcohol In The Brain
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:5/16/2016)... --  EyeLock LLC , a market leader of iris-based ... IoT Center of Excellence in Austin, Texas ... embedded iris biometric applications. EyeLock,s iris authentication ... with unmatched biometric accuracy, making it the most proven ... platform uses video technology to deliver a fast and ...
(Date:4/28/2016)... India , April 28, 2016 ... Infosys (NYSE: INFY ), and Samsung SDS, a ... that will provide end customers with a more secure, ... services.      (Logo: http://photos.prnewswire.com/prnh/20130122/589162 ) , ... services, but it also plays a fundamental part in enabling ...
(Date:4/19/2016)... The new GEZE SecuLogic access ... "all-in-one" system solution for all door components. It can ... door interface with integration authorization management system, and thus ... minimal dimensions of the access control and the optimum ... offer considerable freedom of design with regard to the ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... 2016 Houston Methodist Willowbrook Hospital has ... Association to serve as their official health care ... Willowbrook will provide sponsorship support, athletic training services, ... coaches, volunteers, athletes and families. "We ... Association and to bring Houston Methodist quality services ...
(Date:6/23/2016)... , June, 23, 2016  The Biodesign Challenge ... envision new ways to harness living systems and biotechnology, ... Art (MoMA) in New York City ... 130 participating students, showcased projects at MoMA,s Celeste Bartos ... Paola Antonelli , MoMA,s senior curator of architecture and ...
(Date:6/23/2016)... (PRWEB) , ... June 23, 2016 , ... STACS DNA ... Technical Leader at the Arkansas State Crime Laboratory, has joined STACS DNA as a ... STACS DNA team,” said Jocelyn Tremblay, President and COO of STACS DNA. “In further ...
(Date:6/23/2016)... 2016  Blueprint Bio, a company dedicated to identifying, ... community, has closed its Series A funding round, according ... "We have received a commitment from Forentis Fund ... to meet our current goals," stated Matthew Nunez ... to complete validation on the current projects in our ...
Breaking Biology Technology: