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duminică, 5 august 2012

Mechanism Of Lung Cancer-Associated Mutations Suggests New Therapeutic Approaches

Vanderbilt-Ingram Cancer Center researchers have identified how one of the genes most commonly mutated in lung cancer may promote such tumors.

The investigators found that the protein encoded by this gene, called EPHA3, normally inhibits tumor formation, and that loss or mutation of the gene - as often happens in lung cancer - diminishes this tumor-suppressive effect, potentially sparking the formation of lung cancer. The findings, published July 24 in the Journal of the National Cancer Institute, could offer direction for personalizing cancer treatments and development of new therapies.

The ephrin family of receptors (EPH receptors) comprises a large group of cell surface proteins that regulate cell-to-cell communication in normal development and disease. EPH receptor mutations have been linked to several different cancer types.

Jin Chen, M.D., Ph.D., professor of Medicine, Cancer Biology and Cell & Developmental Biology, studies the cancer-associated roles of these receptors. While her lab has focused primarily on EPHA2 (and its role in promoting breast cancer and tumor blood vessel formation), she decided to look at a different ephrin receptor based on the findings of large genomic screens of lung tumors.

"A 2008 genome-wide study published in Nature identified 26 genes as potential drivers of lung cancer," Chen said. "One of them was EPHA3."

That study and others suggested that mutations in EPHA3 were present in 5 percent to 10 percent of lung adenocarcinomas. However, the studies did not reveal how these mutations might promote tumor formation or progression.

Chen wanted to investigate further whether mutations in EPHA3 were actually "drivers" of lung cancer or just neutral "passenger" mutations and how the mutations might promote tumor growth.

The researchers generated and analyzed 15 different mutations in the receptor. They found that at least two functioned as "dominant negative" inhibitors of the EPHA3 protein - that is, having a mutation in just one allele (or "copy" - humans have two copies of each gene) was enough to inhibit the function of EPHA3.

Chen and colleagues determined that normal or "wild type" EPHA3 inhibits a downstream signaling pathway (the Akt pathway) that promotes cell survival - so, normally, activation of EPHA3 acts as a "brake" on cell growth and survival and induces programmed cell death (apoptosis). When one EPHA3 allele is lost (due to a mutation), the receptor cannot be activated and the Akt pathway remains active, which promotes cell growth and survival.

To determine the impact of EPHA3 mutations on human lung cancer cases, biostatisticians Yu Shyr, Ph.D., and Fei Ye, Ph.D., helped Chen's group identify a mutational signature from existing patient data that strongly correlated with poor patient survival. The team also found that both gene and protein levels of EPHA3 were decreased in patient lung tumors.

While previous studies had linked EPHA3 mutations to lung cancer, the current study is the first to "connect the dots."

"The EPH family is such a big family that nobody had really connected the data from bench top - from the cell and biochemical studies - to human data," Chen said.

Together, the findings suggest that mutations in EPHA3 may be important drivers of a significant fraction of lung cancers. And the research team's identification of the biochemical and cellular consequences of EPHA3 mutations suggests that therapies that target a downstream pathway (such as Akt) might be beneficial for tumors with mutant EPHA3.

Shyr is a professor of Biostatistics, Cancer Biology and Preventive Medicine and is Director of the Center for Quantitative Sciences; Ye is an assistant professor of Biostatistics.

The research was supported by grants from the National Cancer Institute (CA095004, CA114301, CA117915, CA009592, CA090949) of the National Institutes of Health, the Department of Veterans Affairs and the Department of Defense.

Article adapted by Medical News Today from original press release. Source: Source: Vanderbilt-Ingram Cancer Center
Visit our lung cancer section for the latest news on this subject. Source: Vanderbilt-Ingram Cancer Center Please use one of the following formats to cite this article in your essay, paper or report:

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Hope For New Obesity And Diabetes Treatments From Mechanism That Turns White Fat Into Energy-Burning Brown Fat

Columbia University Medical Center (CUMC) researchers have identified a mechanism that can give energy-storing white fat some of the beneficial characteristics of energy-burning brown fat. The findings, based on studies of mice and of human fat tissue, could lead to new strategies for treating obesity and type 2 diabetes. The study was published in the online edition of the journal Cell.

Humans have two types of fat tissue: white fat, which stores excess energy in the form of triglycerides, and brown fat, which is highly efficient at dissipating stored energy as heat. Newborns have a relative abundance of brown fat, as protection against exposure to cold temperatures. In adults, however, almost all excess energy is stored as white fat.

"Turning white fat into brown fat is an appealing therapeutic approach to staunching the obesity epidemic, but it has been difficult to do so in a safe and effective way," said study leader Domenico Accili, MD, professor of Medicine and the Russell Berrie Foundation Professor at CUMC.

White fat can be "browned" with a class of drugs called thiazolidazines (TZDs), which increase the body's sensitivity to insulin. However, TZDs have many adverse effects - including liver toxicity, bone loss, and, ironically, weight gain - which have limited the use of these drugs.

The current study was undertaken to learn more about the function of TZDs, with the ultimate goal of developing better ways to promote the browning of white fat.

Scientists have known that TZDs promote the browning of white fat by activating a cell receptor called peroxisome proliferator-activated receptor-gamma (ppar-gamma), but the exact mechanism was not clear. To learn more, Dr. Accili and his colleagues studied a group of enzymes called sirtuins, which are thought to affect various biological processes, including metabolism.

The researchers had previously shown in mice that when sirtuin activity increases, so does metabolic activity. In the present study, they found that sirtuins boost metabolism by promoting the browning of white fat. "When we sought to identify how sirtuins promote browning, we observed many similarities between the effect of sirtuins and that of TZDs," said lead author Li Qiang, PhD, associate research scientist in Medicine at CUMC.

Sirtuins work by severing the chemical bonds between acetyl groups and proteins, a process known as deacetylation. "So the next question was whether sirtuins remove acetyl groups from ppar-gamma and, indeed, that was what we found," said Dr. Qiang.

To confirm that the deacetylation of ppar-gamma is crucial to the browning of fat, the researchers created a mutant version of ppar-gamma, in effect mimicking the actions of sirtuins. The mutation promoted the development of brown fat - like qualities in white fat.

"Our findings have two important implications," said Dr. Accili. "First, they suggest that TZDs may not be so bad - if you can find a way to tweak their activity. Second, one way to tweak their activity is by using sirtuin agonists - that is, drugs that promote sirtuin activity."

"The truth is, making sirtuin agonists has proved to be a real bear - more promise than fact," he continued. "But now, for the first time, we have a biomarker for good sirtuin activity: the deacetylation of ppar-gamma. In other words, any substance that deacetylates ppar-gamma should in turn promote the browning of white fat and have a beneficial metabolic effect."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. Dr. Accili's paper is titled, "Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Ppar-gamma." The other contributors are Ning Kon (CUMC), Wenhui Zhao (CUMC), Sangkyu Lee (University of Chicago, Chicago, Illinois), Yiying Zhang (CUMC), Michael Rosenbaum (CUMC), Yingming Zhao (University of Chicago), Wei Gu (CUMC), and Stephen R. Farmer (Boston University School of Medicine, Boston, Mass.)
This research was supported by grants from the National Institutes of Health (HL087123, DK58282, DK64773, DK063608, and RR024156).
The authors declare no financial or other conflicts of interest.
Columbia University Medical Center Please use one of the following formats to cite this article in your essay, paper or report:

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joi, 15 decembrie 2011

Gene Mechanism That Stops Colorectal Cancer Modelled In Mice

Featured Article
Academic Journal
Main Category: Colorectal Cancer
Also Included In: Cancer / Oncology; Genetics
Article Date: 15 Dec 2011 - 6:00 PST

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A research team in France has bred a lab mouse with a gene mutation that allows colorectal cancer tumors to grow because the protein coded by the gene is no longer able to trigger cell suicide ("apoptosis"). They hope their discovery will pave the way for developing a treatment that targets the gene so it reactivates apoptosis in cancer cells. They write about their findings in a letter published online on 11 December in the journal Nature.

The team has been working for some time in trying to understand more about cell death, and apoptosis in particular. Once activatived, the mechanism sets the cell onto a self-destruct path. The team's leader is Patrick Mehlen, Director of the DEVweCAN 'Laboratory of Excellence' at the Lyon Cancer Research Centre at the Université de Lyon, Centre Léon Bérard.

For the past 15 years, researchers in this field have been debating about the tumor-suppressing ability of a gene called DCC which in humans codes for a receptor protein known as Deleted in Colorectal Carcinoma. Receptor proteins sit on the surfaces of cells and are receptive to "ligands", special molecules that engage with them and change their behavior, such as activating or silencing signals that do things like control processes inside the cell.

We already know from previous research that DCC expression is either lost or significantly reduced in the majority of advanced colorectal cancers. We also know, that the DCC receptor triggers apoptosis, unless engaged to its ligand, netrin-1.

Mehlen and colleagues proposed that the receptors act like sentinels on the surface of the cells: these sentinels are constantly looking at what is happening in their environment, which is why they are also called "dependence receptors".

While the ligand is engaged, the DCC receptor protein sends out a signal that "all is well", and so does not activate cell death, and the cell survives. But when the ligand is not there, the receptor effectively interprets this as "all is not well", and releases the cell-death trigger.

When you apply this sentinel idea to cancer cells, then it would suggest that the absence of ligands causes the DCC receptors to signal "all is not well", and so set the cells on a path of self-destruction, thus causing the death of rogue cells that would otherwise grow into a tumor.

But, as Mehlen and colleagues point out in their Nature paper, until now, no animal tests have been able to support the idea that this side of DCC is a cause of aggressive cancer development.

So, to investigate the role that DCC-triggered apoptosis might play in the control of tumor development, they used mice already genetically predisposed to develop colon cancer (they have a particular variant of the APC gene), and further modified them so they carried a mutation of DCC whose apoptosis trigger is silent.

They found that the mice spontaneously developed colon cancer.

Mehlen and colleagues describe their findings in the Nature letter:

"Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas."

They conclude that these results show that DCC behaves as a tumor suppressor in that it has the ability to trigger apoptosis in cancer cells.

Mehlen told the press:

"The organism is naturally protected from the development of cancers thanks to the presence of this tumour-suppressing gene."

But, unfortunately, there are some cancer cells that manage to escape this control by blocking the dependence receptor mechanism of DCC.

"That is how we know that the DCC gene is extinguished in most human cancers,' he explained.

The researchers hope it won't be long before this work leads to new target treatments that reactivate cell death in cancer cells. This could apply to other cancers too, such as breast and lung cancer.

"Our group has developed several candidate drugs that reactivate the cell death induced by the DCC receptor in animal models, and we hope to be able to carry out human clinical testing of these candidate drugs in three years' time," said Mehlen.

Mehlen has just been awarded Liliane Bettencourt Schueller Life Sciences Prize, which will help to fund his work.

Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our colorectal cancer section for the latest news on this subject. "DCC constrains tumour progression via its dependence receptor activity"; Marie Castets, Laura Broutier, Yann Molin, Marie Brevet, Guillaume Chazot, and others; Nature published online 11 December 2011; DOI:10.1038/nature10708; Link to Abstract.
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marți, 13 decembrie 2011

Little-Studied Cellular Mechanism Elevated To Potential Drug Target

Main Category: Cancer / Oncology
Also Included In: Pharma Industry / Biotech Industry
Article Date: 13 Dec 2011 - 0:00 PST

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For years, science has generally considered the phosphorylation of proteins -- the insertion of a phosphorous group into a protein that turns it on or off -- as perhaps the factor regulating a range of cellular processes from cell metabolism to programmed cell death. Now, scientists from the Florida campus of The Scripps Research Institute have identified the importance of a novel protein-regulating mechanism -- called sulfenylation -- that is similar to phosphorylation and may, in fact, open up opportunities to develop new types of drugs for diseases such as cancer.

The study was published in an advance online edition of the journal Nature Chemical Biology.

"With this paper, we've elevated protein sulfenylation from a marker of oxidative stress to a bona fide reversible post translational modification that plays a key regulatory role during cell signaling," said Kate Carroll, a Scripps Research associate professor who led the study. "The sulfenyl modification is the new kid on the block."

During periods of cellular stress, caused by factors such as exposure to UV radiation or chronic disease states like cancer, the level of highly reactive oxygen-containing molecules can increase, resulting in inappropriate modification of proteins and cell damage. In sulfenylation, one oxidant, hydrogen peroxide, functions as a messenger that can activate cell proliferation through oxidation of cysteine residues in signaling proteins, producing sulfenic acid. Cysteine, an amino acid (natural protein building block), is highly oxidant sensitive.

Conventional wisdom has long held that if hydrogen peroxide does exist in the cell at any appreciable level, it represents a disease state, not a regulatory event. The new study shows that sulfenylation is actually a positive protein modification, and that it's required for signaling through the pathway, a validation of a long-held belief in some scientific circles that hydrogen peroxide functions as a general signaling molecule, not an oxidative "bad boy" to be eliminated at all costs.

A New Chemical Probe

To explore the process, Carroll and her colleagues developed a highly selective chemical probe -- known as DYn-2 -- with the ability to detect minute differences in sulfenylation rates within the cell.

With the new probe, the team was able to show that a key signaling protein, epidermal growth factor receptor (EGFR), is directly modified by hydrogen peroxide at a critical active site cysteine, stimulating its tyrosine kinase activity.

The technology described in the new paper is unique, Carroll said, because it allows scientists to trap and detect these modifications in situ, without interfering with the redox balance of the cell. "Probing cysteine oxidation in a cell lysate is like looking for a needle in a haystack," she said, "our new approach preserves labile sulfenyl modifications and avoids protein oxidation artifacts that arise during cell homogenization."

As with phosphorylation, future studies on sulfenylation will delve into the exciting discovery of new enzymes, new signaling processes, and new mechanisms of regulation.

Another broad impact of these findings, Carroll said, is to open up an entirely new mechanism to exploit for the development of therapeutics, particularly in cancer. "It should influence the design of inhibitors that target oxidant-sensitive cysteine residues in the future," she said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our cancer / oncology section for the latest news on this subject. The first author of the study, "Peroxide-dependent Sulfenylation of the EGFR Catalytic Site Enhances Kinase Activity," is Candice E. Paulsen of the University of Michigan. Other authors include Thu H. Truong and Stephen E. Leonard of the University of Michigan; and Francisco J. Garcia, Arne Homann and Vinayak Gupta of Scripps Research.
The study was supported by the Camille Henry Dreyfus Teacher Scholar Award and the American Heart Association.
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