A dietary change might be the key to improving colon cancer treatment, according to a new study from the University of Michigan’s Rogel Cancer Center.
Cancer cells need nutrients to survive and grow. One of the most important nutrient sensing molecules in a cell is called mTORC1. Often referred to as the master regulator of cell growth, it allows cells to sense different nutrients and thus grow and proliferate. When nutrients are limited, cells reduce the nutrient sensing cascade and turn off mTORC1.
While mTORC1 is known to be overactive in colon cancer, the key question is whether colon tumors hijack nutrient sensing pathways to trigger the master regulator.
“In colon cancer, when you decrease the nutrients available in the tumors, the cells don’t know what to do. Without the nutrients to grow, they go through some kind of crisis, which leads to mass cell death,” said lead author Yatrik. M. Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology at Michigan Medicine.
The researchers found in cells and in mice that a low-protein diet blocked the nutrient signaling pathway that triggers a master regulator of cancer growth. The results are published in Gastroenterology.
The regulator, mTORC1, controls how cells use nutritional signals to grow and multiply. It is very active in cancers with certain mutations and is known to make cancer resistant to standard treatments. A diet low in protein, and specifically a reduction in two key amino acids, altered nutritional signals through a complex called GATOR.
GATOR1 and GATOR2 work together to keep mTORC1 active. When a cell is high in nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 deactivates mTORC1. Limiting certain amino acids blocks this nutrient signaling.
Previous efforts to block mTORC have focused on inhibiting its carcinogenic signals. But these inhibitors cause significant side effects – and when patients stop taking it, the cancer comes back. The study suggests that blocking the nutrient pathway by restricting amino acids through a low-protein diet offers an alternative to stopping mTORC.
“We knew nutrients were important in regulating mTORC, but we didn’t know how they signaled directly to mTORC. We found that the nutrient signaling pathway is just as important in regulating mTORC as the oncogenic signaling pathway,” said study first author Sumeet Solanki, Ph.D., a researcher at the Rogel Cancer Center.
The researchers confirmed their findings in cells and mice, where they found that limiting amino acids prevented cancer from growing and led to increased cell death. They also looked at tissue biopsies from colon cancer patients, which confirmed elevated mTORC markers correlated with greater resistance to chemotherapy and poorer outcomes. Solanki said this might provide an opportunity to direct the treatment of patients with this marker.
“A low-protein diet will not be a stand-alone treatment. It has to be combined with something else, like chemotherapy,” Solanki said.
The risk of a low-protein diet is that people with cancer often experience muscle weakness and weight loss, which limiting protein might exacerbate.
“Putting cancer patients on a long-term low-protein diet is not ideal. But if you can find key windows — like at the start of chemotherapy or radiation — when patients might be on a low-protein diet for a week or two, we might potentially increase the effectiveness of those treatments,” said Shah.
Further research will refine this concept of therapeutic window to limit amino acids. Researchers will also seek to understand how these pathways create resistance to treatment and whether an inhibitor might block GATOR complexes.
Funding: National Institutes of Health Grants R01CA148828, R01CA245546, R01DK0925201, P30CA046592, P50CA130810, DK034933, F30CA257292-01A1; Department of Defense Grant CA171086, Crohn’s and Colitis Foundation, American Heart Association
