Changing your diet may hold the key to improving colon cancer treatment, according to new research from the University of Michigan Rogel Cancer Center.
Cancer cells need nutrients to survive and grow. One of the most important nutrient-sensing molecules in the cell is called mTORC1. Often referred to as the master regulator of cell growth, it allows cells to sense various nutrients and thus grow and reproduce. When nutrients are limited, cells turn off the nutrient elaboration cascade and turn off mTORC1.
While mTORC1 is known to be hyperactive in colon cancer, a major question is whether colon tumors hijack nutrient-sensing pathways to trigger the master regulator.
“In colon cancer, when you reduce the nutrients available in the tumors, the cells don’t know what to do. Without nutrients to grow, they go through a kind of crisis that leads to massive cell death,” said senior author Yatrik. M. Shah, Ph.D., Horace W. Davenport Professor of Physiology, Michigan Medicine.
The researchers found in cells and in mice that a low-protein diet blocks a nutrient signaling pathway that triggers a master regulator of cancer growth. The results are published in Gastroenterology.
The mTORC1 regulator controls how cells use nutritional signals to grow and reproduce. It is highly active in cancers with certain mutations and is known to make cancer resistant to standard treatments. A low-protein diet, and specifically a reduction in two key amino acids, altered food signals through a complex called GATOR.
GATOR1 and GATOR2 work together to support mTORC1 business. When the cell has plenty of nutrients, GATOR2 activates mTORC1. When nutrients are scarce, GATOR1 shuts down mTORC1. Limiting certain amino acids blocks this nutrient signaling.
Previous efforts to block mTORC have focused on inhibiting cancer-causing signals. But these inhibitors cause significant side effects — and when patients stop taking them, the cancer returns. The study shows that blocking the nutrient pathway by restricting amino acids through a low-protein diet offers an alternative way to shut down mTORC.
“We knew that nutrients were important for regulating mTORC, but we didn’t know how they directly signaled mTORC. We found that the nutrient signaling pathway is just as important for the regulation of mTORC as the oncogenic signaling pathway,” said first author Sumit Solanki, Ph.D., research fellow at the Rogel Cancer Center.
The researchers confirmed their findings in cells and mice, where they saw that amino acid restriction stopped cancer growth and led to increased cell death. They also looked at tissue biopsies from colon cancer patients, which confirmed that high mTORC markers correlated with greater resistance to chemotherapy and worse outcomes. Solanki said this could provide an opportunity to direct treatment for patients with this marker.
“A low-protein diet is not going to 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 can be irritating when protein is restricted.
“Putting cancer patients on a protein-deficient diet is not ideal in the long term. But if you can find key times — like at the start of chemotherapy or radiation — when patients can go on a low-protein diet for a week or two, we could potentially increase the effectiveness of these treatments,” Shah said.
Further studies will clarify this concept of a therapeutic window for amino acid restriction. The researchers will also seek to understand how these pathways create resistance to treatment and whether an inhibitor can 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 Kalitu Foundation, American Heart Association