Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Purdue scientists: To stop cancer, keep your Icmt away from your Ras

29.03.2004


Halting the development of certain pancreatic, ovarian, colon and lung cancers may be possible with therapy based on recent Purdue University research.


These two images show the development of human cells with (above) and without (below) the normal concentration of the protein Ras in their cell membranes. The cells on the right have the protein Ras scattered throughout their cytoplasm, in contrast with the normally developed cells on the left. The absence of the enzyme Icmt prevents Ras from lodging in the membrane, where it ordinarily performs tasks vital to cellular reproduction. Purdue research suggests that preventing Icmt from interacting with Ras during the protein’s development may inhibit the runaway cell growth that is characteristic of cancer, thus leading to new approaches to treating several forms of the disease. (M. Bergo, Journal of Biological Chemistry)



By investigating a single molecule that influences cell growth, a research group in the Purdue Cancer Center, including Brian S. Henriksen, has gained new insight into the chain of events that make some cancer cells divide uncontrollably – insight that may eventually lead to a way to break that chain, stopping cancer in its tracks. The molecule, known as Icmt, has a critical role in the development of Ras, an ordinarily beneficial protein that tells a cell to divide. The research group has determined how to inhibit Icmt’s influence on Ras, without which the protein cannot develop effectively into an instigator of cell growth.

"A tumor can be seen as cells that forget to stop dividing, and misdeveloped Ras is responsible for some instances of uncontrolled growth," said Henriksen, a graduate student in medicinal chemistry and medical pharmacology in Purdue’s School of Pharmacy. "When Ras develops a mutation, it does its job incorrectly, and it becomes a hazard to the body. Our work with Icmt might lead to therapies that could stop errant Ras from causing tumors to progress."


The research was conducted by an interdisciplinary team from two Purdue departments. Co-directing the team are Christine A. Hrycyna, Walther Assistant Professor in the School of Science’s chemistry department and Richard A. Gibbs, associate professor in the School of Pharmacy’s medicinal chemistry and molecular pharmacology department. Jessica L. Anderson (chemistry) and Henriksen are the principal graduate students involved in the project.

Henriksen will present the group’s results at 6 p.m. Sunday (3/28) at the 227th national meeting of the American Chemical Society in Anaheim, Calif.

Ras is a key protein that signals the body’s cells to begin or cease dividing, but for Ras to develop into its complex final form, it undergoes a lengthy chain of modifications that must play out correctly if the protein is ultimately to function properly.

Ras has long been known to be associated with cancer, as it is the incorrectly modified, or mutated, Ras that is behind the uncontrolled cell growth within many cancers. Ninety percent of all pancreatic cancers, one-half of all colon cancers and one-half of the most virulent lung cancers can be traced back to mutant Ras.

"If you want to fight cancer, controlling Ras is an attractive approach," Gibbs said. "Since it requires a chain of modifications, researchers have long taken the approach that if you break the chain, you can stop the cancer."

Earlier attempts to break the chain have met with difficulty because at the point scientists tried to break it in the past, there was always a "back way" – another chemical "route" the body’s enzymes could take to accomplish a given step in the process. Scientists tried to stop mutant Ras from maturing one way, only to find that they had been circumvented by another enzyme that also could get the job done.

"These troubles were actually a tribute to cellular life’s tenacity and survival techniques," Henriksen said. "Life, cancerous life included, will often find a way to overcome adversity. That is why we are so excited about Icmt – it seems to be a weak link in the chain."

The enzyme Icmt, short for isoprenyl cysteine methyltransferase, represents a link in the chain that is a bottleneck of sorts, as there appears to be no back way available to form Ras if Icmt is not present at the right point in the process. Specifically, Icmt’s task – a process called methyl esterification – is to add a small chemical "cap," called a methyl group, to the larger Ras molecule. Without this methyl cap, Ras is unable to anchor itself in the plasma membrane that surrounds a cell, where it must lodge if it is to effect growth commands. So Gibbs and Hrycyna’s labs joined forces to block the biochemical activity of Icmt with small drug molecules, preventing the methyl esterification of Ras and effectively breaking its ability to localize to the plasma membrane.

"This effort depended on both labs," Anderson said. "The Gibbs laboratory brought synthetic expertise, and the Hrycyna laboratory brought large quantities of the protein and the expertise to assay the effects of the inhibitors."

Other groups have shown recently that this lack of a methyl cap causes Ras to localize in the wrong region of the cell and, importantly, results in a Ras protein that cannot support cancerous growth.

"These findings are terrific news for our efforts," said Hrycyna. "If our inhibitor molecules directed at stopping or slowing the activity of Icmt in tumor cells are effective, we should be able to stop the growth of Ras-based cancers."

Hrycyna said she believed the discovery could ultimately throw a wrench into cancer’s operation, but that it was still too early to predict victory.

"We have succeeded in stopping Ras at the protein level and are just beginning to work with whole cells," she said. "This is very different from getting results in animals, and we’re still a long way from human trials. No one should look for this to cure cancer anytime soon, though we are extremely encouraged by these initial results."

But to move the process toward the goal of curing cancer, the group plans to look into other ways of altering Icmt to increase the effect.

"Other ways of changing Icmt might make it even more potent at stopping the development of Ras," Henriksen said. "We’d like to look at all our options and combine them into the most potent inhibitor we can manage – that’s a good goal for the near future."

This research is sponsored in part by a collaborative grant to Gibbs and Hrycyna by the Indiana Elks and the Purdue Cancer Center.

The research group is associated with the Purdue Cancer Center. One of just eight National Cancer Institute-designated basic research facilities in the United States, the center attempts to help cancer patients by identifying new molecular targets and designing future agents and drugs for effectively detecting and treating cancer.

Writer: Chad Boutin, (765) 494-2081, cboutin@purdue.edu

Sources: Brian S. Henriksen, (765) 496-2727, loxarr@hotmail.com
Christine Hrycyna, (765) 494-7322, hrycyna@purdue.edu
Richard Gibbs, (765) 494-1456, rgibbs@purdue.edu
Jessica Anderson, jeanders@purdue.edu

Purdue News Service: (765) 494-2096; purduenews@purdue.edu

Chad Boutin | Purdue News
Further information:
http://news.uns.purdue.edu/html4ever/2004/040328.Henriksen.ras.html

More articles from Health and Medicine:

nachricht Cystic fibrosis alters the structure of mucus in airways
28.06.2017 | University of Iowa Health Care

nachricht Mice provide insight into genetics of autism spectrum disorders
28.06.2017 | University of California - Davis

All articles from Health and Medicine >>>

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

High conductive foils enabling large area lighting

29.06.2017 | Power and Electrical Engineering

Designed proteins to treat muscular dystrophy

29.06.2017 | Life Sciences

Climate Fluctuations & Non-equilibrium Statistical Mechanics: An Interdisciplinary Dialog

29.06.2017 | Seminars Workshops

VideoLinks
B2B-VideoLinks
More VideoLinks >>>