Case Western Reserve University Research Reveals Important Cancer Clues

Ledo

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Jul 31, 2015
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Case Western Reserve University research reveals important cancer clues

CLEVELAND, Ohio -- Supercomputer simulations that predicted the movements of a protein the size of 30 atoms allowed two biophysicists from Case Western Reserve University School of Medicine to uncover important clues to understanding cancer.

This research project, led by Matthias Buck, professor of physiology and biophysics at the school of medicine, showed how cell membranes control the shape and function of an important cancer-causing protein.

The findings were recently described in the journal Structure.

The protein, called K-Ras, attaches to cell membranes and causes healthy cell growth when it's activated by growth hormones secreted by the body. But mutated K-Ras proteins get locked in the "on" position, causing rampant cell growth resulting in cancerous tumors. This is especially prevalent in pancreatic cancer, Buck said.

"The light switch is broken; it's on all the time," Buck explained.

For years, researchers have tried to find way to switch off mutated K-Ras proteins by interrupting growth signals reaching the proteins, Buck said. He and Zhen-Lu (Andrew) Li, a postdoctoral student in the physiology and biophysics department at the Case School of Medicine, tackled the problem by investigating how K-Ras attaches to cell membranes.

The researchers' year-long project found that the protein's function is heavily influenced by lipids, or fatty structures, on the cell membranes. This means that future cancer drugs may need to target both K-Ras and the cell membranes they are attached to, Buck said.

Buck and Li discovered that the composition of lipids in the cell membranes is what makes K-Ras proteins get stuck in the "on" position. If this type of membrane lipid could be kept away from cell membranes, that might prevent K-Ras proteins from flipping "on" and encouraging cancerous cell growth, Buck said.

Lipids are naturally occurring molecules that include fats and make up cell membranes.

K-Ras proteins is only 1/100,000th of an inch - or 30 atoms - in size. To observe something that minuscule, researchers needed to use Case's nuclear magnetic resonance spectrometer, a device that can peer at molecules, Buck said.

Buck and Li spent months running real-time simulations on a specialized computer, dubbed Anton, at the Pittsburgh Supercomputer Center, which is a joint effort of Carnegie Mellon University and the University of Pittsburgh. They also used the High Performance Computing Cluster at Case and the Ohio Supercomputer Center in Columbus, Buck said.

Li's specialty was analyzing the supercomputers' results to reveal the larger picture, Buck said.

Through supercomputer simulations, Buck and Li saw that K-Ras isn't round, but pyramid-shaped with five surfaces that can interact with cell membranes. Supercomputer simulations allowed the researchers to predict, on the atomic level, how K-Ras oriented itself in relation to a cell membrane, as well as the membrane's behavior.

Since lipids are related to fats, it's logical to ask if a patient's diet could affect the lipid-K-Ras interaction. "It doesn't work that way," Buck said.

Instead, future research projects will search for tiny molecules that, when inserted, could turn K-Ras "off." These molecules could be the basis for a future medicine delivered directly to cancer cells, he said.


I wonder if anyone has access to the full study and what it reveals about lipids forming cell membranes. Here is the study from the article.
http://www.cell.com/structure/fulltext/S0969-2126(17)30038-2
 

Soren

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Apr 5, 2016
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1,196
Bump. Anyone know what substances would help limit the Kras gene and turn off the "on" position. This seems to be in line with how the stress lowering substances such as aspirin might work against cancer. They help stop the uncontrolled cellular duplication.
 
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