Blocking cancer—scientists find new way to combat disease

June 21, 2017
Members of Dean Guy's lab (l-r): Jared Hammill, Yizhe Chen, Kip Guy, Gabriela Salinas, Armand Guiguemde and Hoshin Kim. Credit: University of Kentucky

New findings published in Nature Chemical Biology show promise for finding new solutions to treat lung cancer and other deadly diseases. Kentucky continues to lead the nation in incidence and death rates from lung cancer, and the University of Kentucky is committed to reducing these numbers.

According to the National Cancer Institute, cancer is among the leading causes of death worldwide. And of those diagnosed in the United States, accounts for 25 percent of cancer deaths. The numbers are sobering: one out of every two patients diagnosed with lung cancer won't survive past 12 months.

In effort to combat this problem, a collaboration between scientists from University of Kentucky College of Pharmacy, Memorial Sloan Kettering Cancer Center, and St. Jude Children's Research Hospital brings researchers one step closer to a solution.

A compound developed by Dean Kip Guy's lab of UK College of Pharmacy, with research that began at St. Jude Children's Research Hospital, now provides us with a way to block cancer-causing proteins on a cellular level.

The groundwork began more than 10 years ago when Dr. Bhuvanesh Singh, a physician-scientist at Memorial Sloan Kettering Cancer Center, identified that an increase of a protein called DCN1 led to more malignant lung cancers and shorter life spans for his patients. Of the patients he studied, those with high levels of DCN1 succumbed to the disease more quickly than those with normal levels.

Frustrated by their findings, Singh's team set out to study the specifics of DCN1. While DCN1 is a normally occurring protein, his team found that too much of it leads directly to cancer formation. Simply put, a malignant tumor was formed when the amount of DCN1 in a cell was increased. Thus, patients with more DCN1 got sick more quickly and died faster than their counterparts.

Efforts in Brenda Schulman's lab at St. Jude, led by biochemist Daniel Scott, established how DCN1 interacts with other proteins and controls cellular processes. Their key discovery used X-ray crystallography to show that a small modification of the partner protein to DCN1, known as UBE2M was required for DCN1 to work. This modification, N-terminal acetylation (while common) had not previously been shown to be critical to controlling activity of this specific protein. Recognizing the potential for targeting this modification, Shulman reached out to form a collaboration between the three laboratories.

Their goal: to develop a way to stop DCN1 from killing patients.

Understanding the behavior and function of DCN1 was far more ambitious than running simple tests. It was a significant step forward in understanding how proteins within a cell work.

Building upon the science from Schulman's team, Jared Hammill from Guy's lab and Danny Scott from Schulman's lab worked to stop the interactions of DCN1 all together. If DCN1's activity depended on this interaction, then it stood to reason they could create a compound to intervene and stop the interaction from happening.

Guy describes the interaction as a "lock and key model." Scientists have a blank key—which is UBE2M—and a lock, which is DCN1. The key wants to fit into the lock so it's modified until it fits. This modification process is N-terminal acetylation.

"What's the significance?" Guy said. "Well, we're the first people to show that protein interaction controlled by N-terminal acetylation can be blocked. We're essentially jamming the lock with a compound so the key won't fit."

The items jamming that lock are a series of small molecules created in the lab. When the molecules were tested directly in cancer cells, they worked. They effectively blocked DCN1 from binding to UB2EM. After decades of collaborative research, there was finally a barrier between lock and key.

The impact of these findings for healthcare and specifically could be profound.

"We are excited about the implications of this research, which offer us a meaningful solution for addressing diseases like , neurodegenerative disorders, and infection," Schulman said. "It's exciting to collaborate with so many complementary groups of expertise and to watch how Dr. Scott and Dr. Hammill led the team. This research opens many new doors for us."

The collaboration between these three labs could mean relief to many of those suffering from a variety of diseases.

"To have spent decades on this research and have such promising results is truly exhilarating," Singh said. "At the end of the day, what matters most is improving health outcomes for our patients. This is work represents a very important step towards developing a new approach to treat the most difficult of cancers and hopefully increase cure rates."

Explore further: Molecule serves as a key in some protein interactions

More information: Daniel C Scott et al. Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase, Nature Chemical Biology (2017). DOI: 10.1038/nchembio.2386

Related Stories

Molecule serves as a key in some protein interactions

November 4, 2011
Research led by St. Jude Children's Research Hospital scientists has identified an unexpected mechanism facilitating some protein interactions that are the workhorses of cells and, in the process, identified a potential new ...

Before a cure, a crusade to stop lung cancer from spreading

November 11, 2016
The American Cancer Society has reported that lung cancer, which kills more Americans than any other type of cancer, is expected result in an estimated 158,080 deaths in 2016.

Blocking 'lock and key' site of lung cancer proteins could lead to new treatments

November 12, 2013
A Cancer Research UK study reveals that stopping two essential lung cancer proteins from joining together at their 'lock and key' site could lead to new treatments for the disease. The research is published in the journal ...

Targeting SET protein revives p53, potent tumor suppressor, and prevents cancer growth

September 14, 2016
A potent cancer-fighting molecule in our cells can be reawakened by reducing levels of a protein – called SET – that's often found in excess in cancer cells, a new study from Columbia University's Herbert Irving Comprehensive ...

Driver of non-small cell lung cancer, FGFR1, also in 23 percent of small cell lung cancer

April 20, 2015
Significant new treatments are available or in clinical trials for non-small cell lung cancer. The same explosion in treatment options is not true for the disease's cousin, small cell lung cancer, the less common and more ...

Research holds promise for personalized lung cancer treatments

January 12, 2017
New research from scientists at Huntsman Cancer Institute (HCI) at the University of Utah uncovered distinct types of tumors within small cell lung cancer that look and act differently from one another. Scientists also identified ...

Recommended for you

Drug suppresses spread of breast cancer caused by stem-like cells

December 12, 2017
Rare stem-like tumor cells play a critical role in the spread of breast cancer, but a vulnerability in the pathway that powers them offers a strategy to target these cells using existing drugs before metastatic disease occurs, ...

MRI scans predict patients' ability to fight the spread of cancer

December 12, 2017
A simple, non-invasive procedure that can indicate how long patients with cancer that has spread to the brain might survive and whether they are likely to respond to immunotherapy has been developed by researchers in Liverpool.

A new weapon against bone metastasis? Team develops antibody to fight cancer

December 11, 2017
In the ongoing battle between cancer and modern medicine, some therapeutic agents, while effective, can bring undesirable or even dangerous side effects. "Chemo saves lives and improves survival, but it could work much better ...

Insights on how SHARPIN promotes cancer progression

December 11, 2017
Researchers at Sanford Burnham Prebys Medical Discovery (SBP) and the Technion in Israel have found a new role for the SHARPIN protein. In addition to being one of three proteins in the linear ubiquitin chain assembly complex ...

Glioblastoma survival mechanism reveals new therapeutic target

December 11, 2017
A Northwestern Medicine study, published in the journal Cancer Cell, has provided new insights into a mechanism of tumor survival in glioblastoma and demonstrated that inhibiting the process could enhance the effects of radiation ...

Liver cancer: Lipid synthesis promotes tumor formation

December 11, 2017
Lipids comprise an optimal energy source and an important cell component. Researchers from the Biozentrum of the University of Basel and from the University of Geneva have now discovered that the protein mTOR stimulates the ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.