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!
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences