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Research could lead to drugs against cancer

Scientists at the University 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 Dec. 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, a group of scientists headed by John Sondek, assistant professor of pharmacology at the School of Medicine, focused on a specific family called 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 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. Rho family G proteins also are 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 halfway between `on' and `off'," he said. "Now the question is, can we turn the light switch, or G protein, `on' and `off' at will?"

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, he added, 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 and Kent L. Rossman, a pre-doctoral fellow at Lineberger and member of the biochemistry and biophysics department.

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