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Molecular 'switch' in protein may stop the process that helps cancer spread

Hans Vogel, left, Katharine Jensen, and Hiroaki Ishida used magnetic resonance spectroscopy to examine the structure of L-plastin, a protein known to play a role in cancer metastasis. Photo by Riley Brandt, University of Calgary

A discovery made in the Faculty of Science shows potential for a new and different way to prevent cancer metastasis.

Researchers in the Department of Biological Sciences have identified a ‘molecular switch’ in L-plastin, a calcium-binding protein known to play a significant role in tumour metastasis. By deregulating the molecular switch of L-plastin, they were able to block the function of the invading cancerous cells.

Modifying protein can stop cancer from spreading

Study co-author Hans Vogel, PhD, cross-appointed to the Cumming School of Medicine, says the discovery will allow researchers to look at cancer treatment from a completely new perspective, focusing on stopping the metastatic process rather than attacking the solid tumours that have already formed.

Metastasis is the process by which cancer cells break away from the original tumour, travel throughout the body, and establish a new tumour in a different location.

Research has shown that nearly 90 per cent of cancer-related deaths are due to tumour metastasis. “Cancer is typically treated by going after the original tumour,” says Vogel. “Our research may offer a way to try and fight cancer by interfering in metastasis — a completely different process that oncologists and surgeons are still learning how to deal with.”

Using magnetic resonance spectroscopy, the Vogel group examined the protein structure of L-plastin. By analyzing the 3D protein structure, they discovered a new structure that functions as the ‘molecular switch.’ After removing the switch through modifying the L-plastin protein, the researchers found that the protein could no longer function properly.

“Using an inhibitor peptide, we prevented the molecular switch from coming together in its usual way and the regulation of actin bundling was blocked,” explains research associate and co-author Hiroaki Ishida, PhD. “Actin bundling occurs when tumour cells start to metastasize and form the tentacles that allow the cancer cells to move around and spread throughout the body.”

Findings may offer new approach to developing cancer treatments

Vogel anticipates the findings could lead to exciting developments in cancer treatments. “Our study shows that this part of the L-plastin protein can be used as a new anticancer target. If the same process could be accomplished using a drug in humans, we should be able to suppress the ability of tumour cells to become metastatic and spread.”

Co-author Katharine Jensen, a neuroscience grad student who worked on the study as part of her Biochemistry Honours thesis, says understanding the structure of this protein is an important step toward the development of future drug treatments. “With the 3D structure of the molecular switch portion of L-plastin in hand, we can now start on the process of designing or developing new drugs.”

Dr. Eric Hyndman, a clinical assistant professor in the Department of Surgery at the Cumming School of Medicine and co-author and urologist at the Prostate Cancer Centre at Rockyview General Hospital, says the findings present exciting implications for potential clinical applications.

“The science behind this has to do with a very fundamental cell process,” he explains. “It doesn’t only apply to one or two types of cancer. Metastasis happens on all kinds of different malignancies. Whether the cancerous cells are in the prostate or the kidneys, they still have to gain motility before landing somewhere else and causing problems for the patient. So if you can block their ability to gain motility, then you can block their spread.”

The research team has already shown that their approach works in cultured cells, and is moving forward with further testing.

The study was funded by the Arnie Charbonneau Cancer Institute, the Alberta Cancer Foundation, and the Prostate Cancer Centre at the Rockyview Hospital in Calgary. The study was published today in Scientific Reports.

The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases was named in 2008 in honour of Joan Snyder and her parents, who she credits for teaching her the value of philanthropy. It is a group of more than 104 clinicians, clinician-scientists and basic scientists who are impacting and changing the lives of people suffering from chronic diseases, including sepsis, MRSA, cystic fibrosis, type-1 diabetes, inflammatory bowel disease, and chronic obstructive pulmonary disease. For more information on the Snyder Institute for Chronic Diseases, please visit us at www.snyder.ucalgary.ca or follow us on Twitter @SnyderInstitute.