Biology prof investigates role of protein cells in cancer

Normal human cells are programmed to die after they’ve outlived their usefulness. With blood cells, that’s a few days. Cancer cells, however, have figured out a way to circumvent death, at least until York Professor Michael Scheid figures out how to induce suicide in cancer cells or as he puts it, coerce them into undergoing cell death.

“Cells have an intrinsic genetic program to kill themselves when they are no longer needed,” says Scheid. And it’s an orderly process where, if they’re blood cells, after they die they are engulfed by other cells, cut into tiny pieces and disposed of, including the cell’s DNA. "Besides the constant turnover of blood cells, the body can also sense when a skin cell or a brain cell or a breast tissue cell has undergone a genetic error and should die. This process, which is called apoptosis is similar for both blood cells and all of the other tissues of our bodies."

A biologist in the Faculty of Science & Engineering, Scheid was recently awarded $100,000 through the Ontario government’s Early Researcher Award program to continue studying a group of proteins and how they contribute to cancer in humans. His lab investigates signal transduction pathways that control cell division and death and what happens to these pathways when those cells become cancerous.

Left: Michael Scheid next to his lab’s newest and largest microscope

By avoiding death, cancer cells can then mutate and spread to other areas of the body – metastasize – and continue to mutate and move about. “So the cells that were destined to die, if they modified their genetic program they could avoid this death, this self-sacrifice, and that allows them to acquire more genetic errors and therefore they became more and more malignant,” says Scheid.

It was the 1990s when researchers first began to realize that cancer cells circumvent the natural dying process and that there was a whole set of proteins that controlled the process of cell death or apoptosis. It is these protein kinases that Scheid has been researching ever since, particularly PI3K, PDK1, PKB, MEKK3 and ROCK, which all play different roles in keeping a cell alive or signalling it to die.

The key is to find out how cancer cells are escaping death and to figure out what could be done to trick them into undergoing apoptosis. “They’re clever little cells. But if you think about it, your body is composed of somewhere in the range of 70 trillion cells and most cancers occur later on in life because they need decades to acquire mutations, so it’s an exceptionally rare chance event that takes years and years to occur.”

As a graduate student in 1995, Scheid was the lead author on a study that found PI3K was instrumental in controlling the decision for blood cells to undergo apoptosis. In the same year, a group in Boston published similar findings in neurons. “It’s become clear since then that in human cancers this protein, PI3K, is deregulated. It’s turned on when it’s not supposed to be and by having it on it keeps the cell alive,” says Scheid. “So in a tumour, by activating PI3K, it’s given basically the wrong message, ‘you should stay alive, you should continue to grow,’ when really a tumour, since it’s harming the host, would normally be told to undergo cell death.”

Right: Mouse fibroblasts stained for actin (red) and nuclei (blue)

Even when there is genomic damage, which usually sends a strong signal to the cell it needs to die, “a cancer cell has modified its genetic program, including PI3K signalling, to circumvent that signal,” says Scheid. “So my lab studies these pathways to try and understand how we can modulate or how we can externally or artificially tell a cell to undergo death.”

The proteins in a cell can signal another protein telling it to react in a specific way, which then sends another signal to another protein a little further down the line and so on. Tripping up one protein’s signal causes a chain reaction, so if researchers can change the signal of just one protein, the result could be dramatic.

“We’re making discoveries. We’re making progress at the basic level. So it’s been a very successful year, which is the culmination of the work of the last three years since I came to York,” says Scheid. “One of the discoveries was to show that PDK1 undergoes a modification, a phosphorylation event, and that’s a trigger to allow it to shuttle into the nucleus.” That shuttling to the nucleus then activates another protein, PKB, which provides a survival signal; it tells the cell to stay alive. So if that shuttling or survival signal can be shut down, it could be a way to tell the cell it’s time to die, says Scheid.

Another discovery by Scheid and his team at York involves the protein MEKK3. “We discovered a novel phosphorylation of MEKK3 and we showed that MEKK3’s phosphorylation allows its interaction with another molecule (14-3-3) and that interaction is also important in maintaining cell self-survival. It’s like finding tiny pieces in a giant puzzle that gradually come together to form the full picture."

The protein ROCK, on the other hand, is involved in the migration of cells. “That’s important because migration is the principle determinant for metastasis or movement away from the tumour and establishing it somewhere else in the body,” says Scheid. The more that can be discovered about ROCK, the closer researchers are to devising strategies to prevent metastasis.

So where does Scheid and his team go from here? “The next thing is to continue to study the mechanism of survival signalling in cancer cells, which is a primary interest in my lab, to further refine our genetic models to ask questions about PDK1 and also to develop genetic models to understand the regulation of the MEKK3/14-3-3 interaction,” says Scheid. “We need to further refine and break down the model and ask questions that haven’t been addressed yet. So there’s a ton of work to do.”

Above: York PhD candidate Amber Couzens conducts research in Michael Scheid’s biology lab

Scheid’s work is not only applicable to cancer, it has implications for cardiovascular research as well. It’s known that some heart muscle cells, cardiomyocytes, undergo an excess amount of growth, called hypertrophy. During heart disease, the heart wall will inappropriately undergo hypertrophy and Scheid thinks that MEKK3 could be one of the proteins responsible for telling the cardiomyocytes to undergo excessive growth. Understanding more about MEKK3 could help prevent this in the future.

“All this research will lead to innovations that are many years down the road,” says Scheid. “We would hope that in 10 years from now or 20 years from now, we would have more specific drugs that could target molecules such as PDK1, PKB, MEKK3 and PI3K.” Scheid’s research is the starting point to developing treatments. Other researchers take his findings and try to develop compounds to fight the disease. “We’re at the very cutting edge of this biology and it’s been an exciting process so far.”

Scheid was awarded a three-year, $286,842 Canadian Institutes of Health Research grant in 2005, a five-year $160,000 Discovery Grant from the National Sciences and Engineering Research Council of Canada in 2005, and $213,566 from the Canadian Foundation for Innovation in 2006 with matching funds of $213,566 from the Ontario Research Fund.

Scheid co-authored the article “Phosphorylation of MEKK3 at Threonine 294 Promotes 14-3-3 Association to Inhibit Nuclear Factor kB Activation” published in the February 2008 issue of the Journal of Biological Chemistry, and the upcoming “Serine 396 of PDK1 is required for maximal PKB activation” in the Cellular Signalling journal.

By Sandra McLean, YFile writer