Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Drug strategy makes cancer genes get lost in translation

26.01.2007
A new strategy for fighting cancer aims to make its genes get lost in translation, according to a report in the January 26, 2007, issue of the journal Cell, published by Cell Press.

According to the researchers, such a therapy would essentially take advantage of a weakness of the disease: that the majority of growth- and proliferation-related proteins, which cancer depends upon, are encoded by "weak" messenger RNAs (mRNAs). Transcribed from DNA, mRNAs serve as templates for the synthesis of proteins through a process known as translation.

The researchers now report the discovery of a small molecule that targets such weak mRNA, preferentially interrupting its translation into active proteins. As a result, the molecule, called 4EGI-1, effectively silences oncogenes, which have links to cancer. They also found evidence that the small molecule inhibitor exhibits activity against multiple cancer cell lines, including lung and blood cancer cells.

While cancer-promoting proteins may be lost as a result of such treatment, more readily translated "housekeeping" genes--those encoded by "strong" mRNAs that cells need on a regular basis--might continue their activities, said Gerhard Wagner of Harvard Medical School. Therapies targeted at translation might have general use in tackling many forms of cancer, regardless of its genetic origin, given that the uncontrolled growth of cells is a general characteristic of the disease, he added.

The new findings establish a "possible new strategy for cancer therapy," the researchers said. However, they cautioned, the newly described inhibitor is not strong enough for use as a drug in itself. The researchers will next work to chemically modify the inhibitor to enhance its action and screen additional chemical libraries in search of more potent molecules before tests of such a drug in animals could ensue.

Weak mRNAs are translated into proteins less efficiently as a result of long and highly structured, "untranslated regions" at their so-called 5' end, the researchers explained. The lengthy region of weak mRNAs serves as an obstacle for the ribosomal machinery that does the translating, making it a challenge to determine where to begin, he added.

In contrast, strong mRNAs have only short 5' untranslated regions that allow for easier protein formation. The successful translation of weak mRNAs therefore depends more heavily on other protein factors, called initiation factors, to help the process along.

In the current study, the researchers sought to capitalize on the weakness of cancer-related mRNAs by disrupting the interaction between two protein initiation factors, eIF4E and eIF4G.

Assembly of the eIF4E/eIF4G complex is known to have a central role in controlling genes at the level of translation initiation. The complex is normally kept under wraps by still other proteins, the 4E-BPs, which compete with the initiation factors for binding and have tumor-suppressor activity.

The researchers screened thousands of available small molecules for their ability to interfere with the initiation proteins' interaction in a manner similar to the 4E-BPs. The most potent compound identified, 4EGI-1, binds one of the proteins, eIF4E, thereby disrupting the ability of the eIF4E/eIF4G complex to do its job. That interference, in turn, blocked the formation of proteins that require assistance from initiation factors.

"Surprisingly, this compound does not inhibit binding of [the tumor suppressor] 4E-BP1 to eIF4E and instead causes a significant apparent increase in the amount of this protein that is bound," the researchers reported.

Treatment of mammalian cancer cells with the compound had a similar effect on the translation of weak mRNAs to that seen in the initial in vitro tests, they show. What's more, the level of a classic housekeeping gene remained unaffected in treated cells, while expression of two oncogenes, c-Myc and Bcl-xL, declined significantly.

"Our results demonstrate that it is possible to inhibit the protein-protein interaction between eIF4E and eIF4G using small molecules and to establish a methodology that can readily be used to identify new classes of such inhibitors through the screening of compound libraries," the researchers concluded.

The method could lead to new forms of stand-alone or combination cancer therapies, Wagner said, noting that the strategy is "unusual in that it targets a protein-protein interaction, which has not typically been considered a good drug target."

In addition, they added, small-molecule inhibitors of the eIF4E/eIF4G interaction might serve as a useful chemical genetic tool. They noted that such a tool could be used in researchers' investigation of the translational control of gene expression in various cellular processes, such as cell growth and embryonic development.

Erin Doonan | EurekAlert!
Further information:
http://www.cell.com

Further reports about: Inhibitor Initiation Interaction Translation compound eIF4E mRNA

More articles from Life Sciences:

nachricht Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>