Reuben Shaw never planned to work on diabetes—he got into science to study cancer. But in 2003, while a postdoc, he discovered how a cellular hunger circuit links diabetes and cancer. This circuit tells cells to slow down and stop dividing when food—in the form of glucose—is scarce. The finding helps explain why people with type 2 diabetes have an elevated risk of cancer, provides insight into how popular diabetes drugs work, and hints at new ways to treat cancer.
"It was one of those moments," Shaw says of the day he realized that an enzyme important in cancer acted on a key metabolism protein. "I knew this discovery was going to set the course of my career."
One could say that career began when he was a child. Shaw grew up on an old farm in upstate New York and spent lots of time outside. "I had this affinity for nature," he says.
In college, Shaw studied ecology, but molecular biology quickly opened his mind to an unseen universe. He wanted to learn more, so as undergraduate he worked in a cancer laboratory. "There was no turning back," he says, as he grasped that certain master genes controlled cellular behavior.
Years later, Shaw stumbled onto one of those master genes. As a postdoctoral fellow, he was working on an enzyme that suppresses cancer. This enzyme, LKB1, is a kinase, meaning it tags other proteins with groups of phosphate atoms, which in turn sets in motion various bits of cellular machinery. But no one knew which proteins LKB1 targeted. Shaw set about finding out.
After four years of tedious work, he had his answer. LKB1 acted on a protein central to cellular metabolism, called AMPK. "This protein was well studied, and it was known to be a regulator of glucose metabolism," says Shaw. "But no one knew it had any role in cancer."
However, researchers did know that AMPK acted as a hunger sensor. When food—glucose—gets scarce, AMPK becomes activated and pushes the cell into a quiet, low-energy state. Shaw found that LKB1 was the master of this action—it flipped the switch that sent a cell to sleep. And because LKB1 is mutated in many cancers, Shaw had discovered a vital link. "It was so unexpected to find such a direct connection between cancer and metabolism," says Shaw, now at the Salk Institute for Biological Studies. "It wasn't five steps or ten—it was direct, via LKB1."
Shaw then set about "tearing apart the whole signaling pathway" involved with the two proteins. He soon discovered that the most popular diabetes drug in the world, metformin, helps control blood glucose via LKB1.
He now thinks that the connection may explain why people with type 2 diabetes, as well as obese individuals, are at increased risk for major cancers. In type 2 diabetes, metabolism goes awry and cells have difficulty processing glucose. This may affect the LKB1 enzyme, a connection Shaw is exploring.
Shaw plans mouse studies to further investigate this critical connection and to tease out the precise role of each component of the LKB1-AMPK circuit. He also wants to test whether drugs that treat diabetes might also help prevent or treat certain cancers. Already, multiple epidemiological studies inspired by this research have suggested that people who take metformin for diabetes reduce their risk of cancer, just as people who exercise improve their chances of living cancer-free.
Eventually, Shaw hopes his work explains why eating right and exercising benefits the body. "In the end," he says, "we're decoding the molecular basis for these adages."
