The average living cell requires communication skills: it must transmit a constant stream of messages quickly and efficiently from its outer walls to the inner nucleus, where most of the day-to-day decisions are made. But this rapid, long-distance communication system leaves itself open to mutations that can give rise to a “spam attack” that promotes cancer.
Prof. Rony Seger and colleagues at the Weizmann Institute of Science’s biological regulation department have now proposed a way to shut off the overflow of information before it can reach the nucleus. They published their findings recently in Nature Communications.
If the initial promising results hold up, the method could be used to treat a number of different cancers, especially several that develop resistance to current treatments, and it could induce fewer side effects than those treatments do.
Since cells don’t have electronic communication, they use proteins, and they generally manage to send messages quite ably, even getting them through the membranes surrounding the cells and those around the distant nucleus to which the information must ultimately be delivered. A directive from outside the cell – such as a growth factor molecule telling the cell to divide – stops at the cellular membrane. A receptor on the membrane’s outer surface accepts the message and passes its signal to the inner side. From there, “if the molecules were human messengers, they would have to transverse the equivalent of some 70 km to get from the outer membrane to the nucleus,” said Seger.
Instead of sending messages all the way by a single courier molecule, the cell speeds things up with a sort of relay in which the message gets handed from one molecule to another. This whole membrane-to-nucleus communications system is known as a cellular signaling pathway, and there are about 15 different pathways for transferring the cell’s main internal messaging.
Seger has identified a number of the proteins involved in these pathways, especially in one particular pathway, called the MAPK/ERK cascade, which is involved in cancer. Dysregulation of this pathway shows up in some 85 percent of all cancer types. In normal cells, the messages these proteins pass along are normally delivered in spikes: the last protein in the relay slips into the cell nucleus, delivers the memo, and slips out again.
But following certain mutations, the previously useful message becomes spam: it gets sent over and over, flooding the nucleus’s “inbox.” The response to this “spam attack” can be disastrous; in the case of such messages as those to grow or divide, the result may be cancerous.
A crucial step in this pathway takes place when a molecule called ERK undergoes a transformation that enables it to pass through the membrane surrounding the nucleus.
Seger has researched this step in depth, revealing a complex process that must occur for ERK to get its message across.
Seger realized that an effective nuclear “spam filter” on the ERK pathway would involve blocking just this step, thus preventing specific ERK “messages” from getting into the nucleus. He and his team designed a variety of small molecules to enter the cell and block the transfer of ERK molecules into the cell’s nucleus.
Working with Dr. Michal Besser of the Sheba Medical Center, they grew cells from different cancers in culture and then added the different molecules to see which of them would best target ERK.
The team identified one potential drug molecule that performed quite well, even causing many of the cancer cells to die. Seger says that the cancer cells become “addicted” to the constant flow of ERK signals, so adding a filter that cuts this signal off causes them to die.
Importantly, this molecule did not affect normal cells, suggesting that it mainly targets the cancer process and therefore might have fewer side effects than the present chemotherapy drugs.
The next step was to test the molecule in mouse models of human cancers. In some of the cancers, says Seger, “the molecule worked even better in the animal models than it did in culture. The cancers disappeared within days and did not return.” In addition, the fact that the molecules do not destroy the ERK but only stop it from entering the nucleus may be good news for healthy cells, as the ERK can still send a “delivery receipt” back up the relay to the receptors so they don’t try to resend the message.
One of the cancers that the molecule eradicated in the experiments was melanoma, an often-fatal skin cancer with few available treatments. The drugs currently used for melanoma, said Seger, usually work for a while and then the cancer becomes resistant to them. He envisions the new molecule being added to the drug regimen, in rotation with others so that resistance cannot develop. All in all, the molecule was completely effective in eliminating around a dozen of the cancers the team tested, and many others showed a decline, if not complete destruction, of the cancer cells.
The method of designing small molecules that can get inside cells and stop certain messages before they become “spam” might be useful in treating other diseases, in addition to cancer.
“Every pathway is associated with a different disease,” noted Seger. “The trick is to find the molecules that can selectively target just one stage in the process.”
He and his team are currently experimenting with molecules to block a different pathway, one that is associated with autoimmune disease.
LISTEN TO YOUR MOTHER ABOUT VEGGIES Something as easy as adding more spinach, kale, collards and mustard greens to your diet could help slow cognitive decline, according to new research. The study also examined the nutrients responsible for the effect, for the first time linking vitamin K consumption to slower cognitive decline.
“Losing one’s memory or cognitive abilities is one of the biggest fears for people as they get older,” said Dr. Martha Clare Morris of Chicago’s Rush University Medical Center and leader of the research team.
“Since declining cognitive ability is central to Alzheimer’s disease and dementias, increasing consumption of green leafy vegetables could offer a very simple, affordable and non-invasive way of potentially protecting your brain from Alzheimer’s disease and dementia.”
The researchers tracked the diets and cognitive abilities of more than 950 older adults for an average of five years and saw a significant decrease in the rate of cognitive decline for study participants who consumed greater amounts of green leafy vegetables. People who ate one to two servings per day had the cognitive ability of a person 11 years younger than those who consumed none.
When the researchers examined individual nutrients linked with slowing cognitive decline, they found that vitamin K, lutein, folate and beta-carotene were most likely helping to keep the brain healthy.
“Our study identified some very novel associations,” said Morris, who presented the research at the American Society for Nutrition annual meeting. “No other studies have looked at vitamin K in relation to change in cognitive abilities over time, and only a limited number of studies have found some association with lutein.” Other studies have linked folate and beta-carotene intake with slower cognitive decline.
Thee participants, whose age averaged 81, reported their daily food and beverage intake by answering a detailed 144-item questionnaire at the beginning of the study and were followed for two to 10 years.
“With baby boomers approaching old age, there is huge public demand for lifestyle behaviors that can ward off loss of memory and other cognitive abilities with age,” said Morris. “Our study provides evidence that eating green leafy vegetables and other foods rich in vitamin K, lutein and beta-carotene can help to keep the brain healthy to preserve functioning.” In addition to green leafy vegetables, other good sources of vitamin K, lutein, folate and beta-carotene include brightly colored fruits and vegetables