Crystal structure of protein interaction could lead to new drugs against cancer

December 05, 2000

Chapel Hill - Scientists at the University of North Carolina at Chapel Hill for the first time have identified the three dimensional crystal structure of two cellular proteins that when bound together play a key role in triggering the spread of cancer cells.

The new findings are published in the December 7 issue of the international science journal Nature. They should help pave the way for deciphering exactly how this protein complex normally functions in the cell's molecular pathway and what can go wrong when either protein is mutated. Given this information, future drug discovery efforts can be aimed at targeting the interaction between specific proteins involved in making cancer cells invasive while causing little or no unwanted side effects.

In their research, scientist headed by John Sondek, PhD, assistant professor of pharmacology at UNC-CH School of Medicine focused on a specific family G proteins important in cellular growth control and architecture.

"You can think of a G protein as a light switch," Sondek said. "And there are many of these proteins in your body that are controlling numerous functions, depending on whether they're switched 'on' or 'off'."

The UNC researcher studies the Rho family of G proteins, which normally help regulate such important functions as cell shape, division, movement, proliferation - virtually every aspect of cellular change and development. In addition, Rho family G proteins are also implicated in malignant growth transformation.

According to Sondek, activation of these G proteins depends on the molecular signal they receive from other proteins called guanine nucleotide exchange factors or GEFs. "If GEFs are in their active form, they in turn activate the G protein. Trouble occurs when you get a perpetual 'on' state for these G-proteins, which can lead to malignancies."

Here, the 'on' position of the light switch occurs when the G protein is bound to the small molecule guanosine triphosphate or GTP. Through X-ray crystallography methods, which initially involve purification of the proteins, Sondek's team has determined the molecular structure of a Rho family G protein bound to its activator, the T-lymphoma and invasion metastasis factor, or Tiam1.

"This structure is essentially the G protein light switch half way between 'on' and 'off.' Now the question is, can we turn the light switch, or G protein, 'on' and 'off' at will?" asks Sondek.

A member of the UNC Lineberger Comprehensive Cancer Center and a Pew Biomedical scholar, Sondek has been studying Tiam1 because when it is over-expressed, it causes invasion and spreading of a lymphoma that is not normally invasive.

"Our work basically provides the details for understanding how these G proteins are activated," he said. "In terms of its clinical implications, Tiam1 is known for its ability to induce normally non-invasive T-lymphoma cancer cells to become invasive, and has subsequently been shown to produce experimental cancer metastasis in mice. A major difficulty in cancer treatment arises when cancer cells leave the site of the primary tumor and invade other parts of the body."

Moreover, notes the researcher, Tiam1 is present and in virtually all tumor cells analyzed. Sondek's long-term research will involve determining the structures of other G proteins and their activators to build up a set of data to which rational drug design can be applied. The structures will highlight points of protein interaction between the G proteins that may be targeted pharmacologically.

Co-authors of the Nature report are American Cancer Society fellow David Worthylake, PhD and Kent L. Rossman, a pre-doctoral fellow of the Lineberger Comprehensive Cancer Center and member of the biochemistry and biophysics department.
-end-
Note to media: Contact Dr. Sondek at 919-966-7530 (sondek@med.unc.edu) For a color jpg image of the crystal structure, contact Leslie H. Lang, UNC School of Medicine, 919-843-9687 or E-mail: llang@med.unc.edu

University of North Carolina Health Care

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.