A change in diet may be the key to improving colon cancer treatment, according to a new study from the University of Michigan Rogel Cancer Center.
Cancer cells need nutrients to survive and grow. One of the essential nutrient sensing molecules in the cell is called mTORC1. Often called the master of cell growth regulation, it allows cells to sense different nutrients and thereby grow and reproduce. When nutrients are limited, cells go down the nutrient sensing cascade and turn off mTORC1.
Although mTORC1 is known to be hyperactive in colon cancer, the key question is whether colon tumors hijack nutrient-sensing pathways to turn on the supreme regulator.
In colon cancer, when you reduce the nutrients available to 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.”
Yatrik M. Shah, Ph.D., senior author, Horace W. Davenport University Professor of Physiology at Michigan Medicine
Researchers found in cells and mice that a low-protein diet blocked the nutrient signaling pathway that triggers the master control of cancer growth. Results are published in Digestive anatomy.
The regulator, mTORC1, controls how cells use nutrient signals to grow and reproduce. It is very active in cancers with specific mutations and is known to cause cancer to become resistant to conventional treatments. A low-protein diet, and specifically a reduction in two key amino acids, altered nutrient signaling through a complex known as GATOR.
GATOR1 and GATOR2 work together to keep mTORC1 in business. When a cell has enough nutrients, GATOR2 activates mTORC1. When nutrients are low, GATOR1 turns off mTORC1. Limiting certain amino acids blocks this nutrient signaling.
Previous attempts to inhibit mTORC have focused on blocking its oncogenic signaling. But these inhibitors cause significant side effects — and when patients stop taking them, the cancer comes back. The study suggests that blocking the nutrient pathway by limiting amino acids through a low-protein diet offers another way to shut down mTORC.
“We knew that nutrients were important in mTORC regulation, but we didn’t know how they directly signal to mTORC. We found that the nutrient signaling pathway is just as important for regulating mTORC as the oncogenic signaling pathway,” said Sumeet Solanki, first author of the study. Ph.D., researcher at the Rogel Cancer Center.
Researchers confirmed their results in cells and mice, where they saw that limited amino acids stopped the growth of cancer and led to increased cell death. They also looked at biopsies from colon cancer patients, which confirmed high levels of mTORC correlated with greater resistance to chemotherapy and worse outcomes. Solanki said this could provide an opportunity to target therapy for patients with this marker.
“A low-protein diet will not be a stand-alone treatment. It will have to be combined with something else, such as chemotherapy,” said Solanki.
The danger of a low-protein diet is that people with cancer often experience muscle weakness and weight loss, which restricting protein could exacerbate.
“Putting cancer patients on a low-protein diet long-term is not ideal. But if you can find a key window – like at the beginning of chemotherapy or radiation – when patients could go on a low-protein diet for a week or two, we could potentially increase the effectiveness of these treatments, Shah said.
Further research will refine this concept of a therapeutic window for amino acid restriction. Researchers will also seek to understand how these pathways create resistance to treatment and whether an inhibitor could block the GATOR complexes.
Solanki, S., and more. (2022) Dysregulated amino acid sensing drives colon cancer growth and metabolic reprogramming leading to cancer resistance. Digestive anatomy. doi.org/10.1053/j.gastro.2022.11.014.