Latest Science Updates

When researchers look inside human cancer cells for the whereabouts of an important tumor-suppressor, they often catch the protein playing hooky, lolling around in cellular broth instead of muscling its way out to the cells’ membranes and foiling cancer growth.

This phenomenon of delinquency puzzled scientists for a long time — until a cell biologist in the Johns Hopkins University

School of Medicine felt compelled to genetically grab the protein by the tail and then watched as it got back to work at tamping down disease.

“It was curious that when we removed its tail, the protein suddenly was unhindered and moved out to the membrane and became active,” says Meghdad Rahdar, a graduate student in pharmacology.

The discovery, published Dec. 15 online at the Proceedings of the National Academy of Sciences, represents a potential new approach to cancer therapy, according to Peter Devreotes, Ph.D., professor and director of cell biology at Johns Hopkins.

“A long-term goal is to find a drug that does the equivalent of our bit of genetic engineering,” he says.

The flexible tail contains a cluster of four amino acids — the building blocks of proteins — that regulate this tumor suppressor known as PTEN. When chemically modified, these amino acids act to “glue” the tail back to the body of PTEN and prevent the attachment of PTEN to the membrane. By genetically removing PTEN’s tail, or manipulating the cluster of four amino acids so that they cannot be modified, the researchers persuaded PTEN to move to the cell membrane where it goes about its tumor-suppressing business of degrading a molecular signal called PIP3 that causes errant cell growth.

“As far as I know, I haven’t seen anyone activate a tumor suppressor, but we seem to have done it genetically,” Rahdar says.

While genetically engineering cancer cells in the human body is neither practical nor safe, manipulating such unbinding of PTEN with drugs is a viable alternative to guard against cell overgrowth, the hallmark of cancer, the Hopkins scientists say.

In many tumors, PTEN is simply not present. In others, it’s there, but a key enzyme that produces PIP3 is over-activated. The Hopkins team already has shown the first evidence that adding the modified PTEN to cells that lack PTEN not only restores normal enzyme levels but ramps up PTEN activity and quells the cell growth signal.

The research was supported by the National Institutes of Health.

In addition to Rahdar and Devreotes, authors on the paper are Takanari Inoue, Tobias Meyer, Jin Zhang and Francisca Vazquez, all of Johns Hopkins.

source-www.sciencedaily.com

Kidney cancer is typically without symptoms until it has spread to other organs, when it is also the most difficult to treat. Newer chemotherapies show great promise for extending survival during later disease stages, but they can also be highly toxic.

In one of the first discoveries of its kind, UC Davis Cancer Center researchers have identified ways to block a cancer gene's own repair mechanism and, in so doing, help make chemotherapy for kidney cancer more effective and better tolerated.

"Cancer cells are notorious in their ability to rapidly create copies of themselves. While the latest medications slow down that process, they do not tend to be curative and have many side effects," said Robert Weiss, a UC Davis professor of nephrology and chief of nephrology at the Sacramento VA Medical Center. "We wanted to find ways to help make chemotherapeutics as effective as possible at the lowest doses possible."

Newer medications work by destabilizing cancer cells at the DNA level, which reduces their ability to replicate. Knowing that the p21 gene has an important role in restoring cancer cell DNA and potentially circumventing the benefits of those treatments, Weiss sought to identify compounds that could interrupt this pathway.

The team tested thousands of compounds and 12 were found to bind to the recombinant protein p21. Additional tests showed that three of those compounds decreased p21 expression, blocking kidney cancer cells' ability to mend and making them more responsive to DNA-damaging treatments.

"The results are very exciting, especially given how difficult kidney cancer has so far been to treat," Weiss said. "Our work offers hope that in the future these p21 inhibitors can be refined and used in concert with other conventional as well as novel cancer treatments to increase the comfort and life spans of patients with kidney cancer."

For future studies, Weiss will focus on the three candidate compounds to determine the lowest possible concentrations at which they remain effective and to further optimize their anti-cancer properties. He will then test those compounds with standard treatments in animal models and, ultimately, in human trials.

"The goal is to find new approaches to treating a cancer for which few options currently exist and make those approaches available in clinical settings as quickly as possible," he said.

The outcome is published in the current issue of Cancer Biology and Therapy. Other UC Davis study authors were See-Hyoung Park, Xiaobing Wang, Riuwu Liu and Kit Lam. Their research was supported by the National Cancer Institute, the U.S. Department of Veterans' Affairs, the Morris Animal Foundation, the National Institutes of Health and the National Science Foundation.

source-www.sciencedaily.com

Researchers from Duke University Medical Center have identified a variation in a particular gene that increases susceptibility to early coronary artery disease. For years, scientists have known that the devastating, early-onset form of the disease was inherited, but they knew little about the gene(s) responsible until now. The results are published January 2 in the open-access journal PLoS Genetics.
In a previous study, a region on chromosome 7 was linked to coronary artery disease (CAD). More recently, the researchers focused on identifying the gene in this region that confers risk of early-onset CAD and identified it as the neuropeptide Y (NPY) gene. NPY is one of the most plentiful and important proteins in the body and is a neurotransmitter related to the control of appetite and feeding behavior, among other functions.
The current research, led by Svati Shah and Elizabeth Hauser, found evidence for six related variations in the NPY gene that show evidence of transmission from generation to generation and association across a population of early-onset CAD patients.
The researchers evaluated 1,000 families for CAD or evidence of a true heart attack, as part of the GENECARD study put together by the Duke University Cardiology Consortium. An independent, nonfamilial study used a collection of samples of nearly everyone who had an angiogram at Duke since 2001. Co-authors William Kraus and Christopher Granger founded this repository, called CATHGEN, which is now nearing 10,000 subjects. The nonfamilial work showed a strong relationship between the NPY genetic variants associated with coronary disease.
The genetic results were even stronger in patients with onset of CAD before the age of 37. "We showed a strong age effect," said Hauser. "If one has the NPY gene variants in one of two copies (from mother and father), then you may develop coronary disease earlier."
"These young patients are a vulnerable population on whom CAD has a significant long-term impact, but they are particularly hard to identify and therefore to initiate preventive therapies for," Shah said. "These and other genetic findings may help us in the future to identify these patients prior to development of CAD or their first heart attack."
The group further examined NPY levels in blood and found that, among the six NPY variants, there is a single-nucleotide change of the DNA code on the NPY promoter region of the gene – the part of the gene that turns it on and off. This single-letter change was associated with higher NPY levels, suggesting that this was the functional change that predisposes a person to early onset CAD.
"If you had 1 or 2 copies of this mutant version of the gene, there could be a change in NPY level," Shah said. "The concept is that small changes over time can promote atherosclerosis (hardening of the arteries) at a very young age."
Mouse studies subsequently confirmed that the NPY pathway promotes atherosclerosis. The next step may be to examine the children of the people who were studied. Studying the heterogeneity among individuals with early-onset disease – overweight versus normal weight families, for example – will also be important.
source-www.eurekalert.org

Ovarian cancer recurrence tied to gene's role in promoting autophagy

HOUSTON – A single tumor-suppressing gene is a key to understanding, and perhaps killing, dormant ovarian cancer cells that persist after initial treatment only to reawaken years later, researchers at The University of Texas M. D. Anderson Cancer Center report in the December Journal of Clinical Investigation.

The team found that expression of a gene called ARHI acts as a switch for autophagy, or self-cannibalization, in ovarian cancer cells. Often a mechanism for cancer cell death, in this case "self-eating" acts as a survival mechanism for dormant cancer cells.

"Prolonged autophagy is lethal to cancer cells, but a little autophagy can help dormant cancer cells survive, possibly by avoiding starvation," said senior author Robert Bast, M.D., vice president for translational research at M. D. Anderson.

"Dormant cells are a major problem in ovarian cancer, breast cancer and other malignancies," Bast said. "We often see ovarian cancer removed, leaving no remaining sign of disease. After two or three years, the cancer grows back. If any remaining cancer cells had continued to grow normally, the disease should have returned in weeks or months.

"So the assumption is that some cells remain dormant without dividing and without developing a blood supply, but the mechanism for this has not been well understood," Bast said.

Bast and colleagues focused on ARHI, short for aplasia Ras homolog member I, a gene found in normal cells, but that is underexpressed in 60-70 percent of ovarian cancers.

When normal levels of ARHI were restored to ovarian cancer cells in the laboratory, autophagy was induced and cancer cells died within a few days.

When the experiments moved to human ovarian cancer grafts in mice, a different effect was noted. ARHI stopped tumor growth and induced autophagy, but did not kill the cancer cells. When ARHI was turned off at 4 to 6 weeks, the ovarian cancer cells grew rapidly.

"Cancer cells had remained viable during ARHI-induced growth arrest and autophagy, which is consistent with a dormant state," Bast said. "When we blocked autophagy with chloroquine, a drug also used to treat malaria, regrowth of the cancers was inhibited, suggesting that autophagy had helped the cancer cells to survive in the absence of a blood supply."

Autophagy is a cellular survival mechanism that protects cells in a variety of ways. In the case of stress caused by lack of nutrients, autophagy is roughly comparable to a person burning body fat to survive the absence of food.

Several protein survival factors were detected within the microenvironment of the ovarian cancer grafts that could prevent autophagy-induced death of ovarian cancer cells in the laboratory. Blocking these survival factors could provide a novel strategy for eliminating dormant ovarian cancer cells and curing more patients.

Whether cancer cells die an autophagic death, remain dormant or exit dormancy to grow again depends on the balance between ARHI's tumor-suppressing activity and the anti-autophagic and proliferative activity of these environmental survival factors, the authors note.

The ARHI-autophagy pathway also provides an inducible model for tumor dormancy. Lack of a model has hindered understanding of dormant cells and the development of treatments to eliminate them, Bast noted.

source-www.eurekalert.org