Tag Archives: protein

cancer

TGen identifies key lung cancer enabler

Researchers at the Translational Genomics Research Institute (TGen) have discovered a protein, Mcl-1, that helps enable one of the most common and deadly types of cancer to survive radiation and drug treatments.

Non-small cell lung cancer (NSCLC) makes up about 85 percent of the nearly 160,000 Americans expected to die this year from lung cancer, which by far kills more patients than any other type of cancer; accounting for more than 1 in 4 cancer deaths in the U.S. annually. The 5-year survival rate for advanced NSCLC is less than 10 percent.

In the absence of more effective targeted therapies, most lung cancer patients currently rely on platinum-derived chemotherapeutics, such as cisplatin, or radiation therapy.

Previous TGen studies have shown that excessive activation of a cellular signaling mechanism known as TWEAK-Fn14 is linked to the survival and spread of cancer cells.

In a new laboratory study published in the scientific journal Molecular Cancer Research, TGen investigators found that a protein called Mcl-1 helps enable TWEAK-Fn14, which in turn helps protect NSCLC tumors from being destroyed by radiation and drugs.

“Our study demonstrates that the expression of Mcl-1 is necessary to promote the TWEAK-mediated survival of NSCLC tumor cells,” said Dr. Timothy Whitsett, an Assistant Professor in TGen’s Cancer and Cell Biology Division, and the study’s lead author. “By deactivating Mcl-1, we believe we can give these lung cancer patients a better response to standard therapy.”

Employing a drug called EU-5148, laboratory researchers using lung cancer cell lines found they could block Mcl-1 function and halt the TWEAK-Fn14 cellular signaling mechanism.

“Inhibition of Mcl-1 function enhanced chemo- and radio-sensitivity in NSCLC cells. The depletion of Mcl-1 … was sufficient to abrogate the protective effects conferred on lung tumor cells by TWEAK-Fn14 signaling,” according to the study, Mcl-1 Mediates TWEAK/Fn14-induced Non-small Cell Lung Cancer Survival and Therapeutic Response, published online Jan. 27, and awaiting print publication on April 14.

“This work positions both the TWEAK-Fn14 cellular pathway and the Mcl-1 protein as potential therapeutic interventions,” said Dr. Nhan Tran, an Associate Professor in TGen’s Cancer and Cell Biology Division, and the study’s senior author. “Our evidence shows that, if we can bypass these mechanisms, it will be more difficult for these lung cancer cells to evade therapies.”

The study concludes that additional research of Mcl-1 and TWEAK-Fn14 mechanism is needed, eventually leading to clinical trials and more effective treatments that could reduce lung cancer mortality.

The drug, EU-5148, was provided by Eutropics Pharmaceuticals, based in Cambridge, Mass.

Cancer Treatment Centers of America (Goodyear) also contributed to this study.

The study was funded by the National Institutes of Health (NIH).

stem.cell

TGen-led study finds link to Parkinson’s disease

The absence of a protein called SMG1 could be a contributing factor in the development of Parkinson’s disease and other related neurological disorders, according to a study led by the Translational Genomics Research Institute (TGen).

The study screened 711 human kinases (key regulators of cellular functions) and 206 phosphatases (key regulators of metabolic processes) to determine which might have the greatest relationship to the aggregation of a protein known as alpha-synuclein, which has been previously implicated in Parkinson’s disease. Previous studies have shown that hyperphosphorylation of the α-synuclein protein on serine 129 is related to this aggregation.

“Identifying the kinases and phosphates that regulate this critical phosphorylation event may ultimately prove beneficial in the development of new drugs that could prevent synuclein dysfunction and toxicity in Parkinson’s disease and other synucleinopathies,” said Dr. Travis Dunckley, a TGen Assistant Professor and senior author of the study.

Synucleinopathies are neurodegenerative disorders characterized by aggregates of α-synuclein protein. They include Parkinson’s, various forms of dementia and multiple systems atrophy (MSA).

The study — SMG1 Identified as a Regulator of Parkinson’s disease-associated alpha-Synuclein Through siRNA Screening — was published today in the journal PLOS ONE.

By using the latest in genomic technologies, Dr. Dunckley and collaborators found that expression of the protein SMG1 was “significantly reduced” in tissue samples of patients with Parkinson’s and dementia.

“These results suggest that reduced SMG1 expression may be a contributor to α-synuclein pathology in these diseases,” Dr. Dunckley said.

TGen collaborators in this study included researchers from Banner Sun Health Institute and Mayo Clinic Scottsdale.

Tissue samples were provided by the Banner Brain and Body Donation Program. The study was funded by the Arizona Parkinson’s Disease Consortium, which includes Mayo Clinic Scottsdale, Sun Health Research Institute, Barrow Neurologic Institute, Banner Good Samaritan Medical Center, Arizona State University, and TGen.

The study is available at: http://dx.plos.org/10.1371/journal.pone.0077711.