A new study from the University of Michigan’s Rogel Cancer Center finds that dietary changes could be key to improving colon cancer treatment.
Cancer cells need nutrients to survive and grow. One of the most important nutrient-sensing molecules in the cell is called mTORC1. Often called the master regulator of cell growth, it allows cells to sense different nutrients and thus grow and reproduce. When nutrients are limited, cells turn off the nutrient-sensing cascade and turn off mTORC1.
While mTORC1 is known to be overactive in colon cancer, a key question is whether colon tumors hijack the nutrient-sensing pathways to release the master regulator.
“In colon cancer, when you reduce the nutrients available in the tumours, the cells don’t know what to do. Without the nutrients to grow, they go through a kind of crisis, which leads to massive cell death,” said senior researcher Yatrik. Shah, MD, Horace W. Davenport Professor of Physiology at Michigan Medicine.
In cells and mice, the researchers found that a low-protein diet inhibited a nutrient signaling pathway that triggers a key regulator of cancer growth. The results are published in Diseases of the digestive system.
The regulator, mTORC1, controls how cells use nutritional signals for growth and reproduction. It is highly active in cancers with certain mutations and is known to cause cancers to become resistant to standard therapies. A low-protein diet, specifically reducing two key amino acids, altered food signaling through a compound called GATOR.
GATOR1 and GATOR2 work together to keep mTORC1 in action. When a cell has too many nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 deactivates mTORC1. Reducing certain amino acids blocks these nutritional signals.
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 suggests that blocking the nutrient pathway by limiting amino acids through a low-protein diet provides an alternative way to shut down mTORC.
“We knew that nutrients are important in mTORC regulation but we didn’t know how they signal directly to mTORC. We discovered that the nutrient signaling pathway is just as important to mTORC regulation as the cancer signaling pathway,” said Sumit Solanki, first author of the study. PhD researcher at the Rogel Cancer Center.
The researchers confirmed their findings in cells and mice, where they saw that limiting the amino acid prevents cancer from growing and leads to increased cell death. They also looked at tissue biopsies from colon cancer patients, which confirmed high mTORC markers associated with more resistance to chemotherapy and worse outcome. Solanke said this could provide an opportunity to target treatment for patients with this sign.
“A low-protein diet is not going to be a standalone treatment. It has to be combined with something else, like chemotherapy,” Solanki said.
The danger with a low-protein diet is that people with cancer often experience muscle weakness and weight loss, which can lead to protein overload.
“Putting cancer patients on a low-protein diet long-term is not ideal. But if you can find key windows — such as the start of chemotherapy or radiation — where patients can go on a low-protein diet for a week or two, it would be better,” Shah said. We are likely to increase the effectiveness of these therapies.”
Additional research will refine this concept of the therapeutic window for amino acid reduction. Researchers will also seek to understand how these pathways create resistance to treatment and whether an inhibitor can block GATOR complexes.
Funding: NIH grants R01CA148828, R01CA245546, R01DK0925201, P30CA046592, P50CA130810, DK034933, F30CA257292-01A1; Grant CA171086, Department of Defense, Crohn’s and Colitis Foundation, American Heart Association