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Changing your diet could be a key to improving colorectal cancer treatment
Changing your diet could be a key to improving colorectal cancer treatment, finds a new study from the University of Michigan Rogel Cancer Center. Cancer cells need nutrients to survive and grow. One of the essential nutrient-sensitive molecules in a cell is called mTORC1. Often referred to as the master regulator of cell growth, it allows cells to sense various nutrients and thereby grow and multiply. When nutrients are limited, cells down-select the nutrient-sensing cascade and turn off mTORC1. While mTORC1 is known to be hyperactive in colon cancer, the key question is whether colon tumors hijack nutrient sensing pathways to destroy the master regulator...
Changing your diet could be a key to improving colorectal cancer treatment
Changing your diet could be a key to improving colorectal cancer treatment, finds a new study from the University of Michigan Rogel Cancer Center.
Cancer cells need nutrients to survive and grow. One of the essential nutrient-sensitive molecules in a cell is called mTORC1. Often referred to as the master regulator of cell growth, it allows cells to sense various nutrients and thereby grow and multiply. When nutrients are limited, cells down-select the nutrient-sensing cascade and turn off mTORC1.
While mTORC1 is known to be hyperactive in colon cancer, the key question is whether colon tumors hijack nutrient sensing pathways to activate the master regulator.
In colon cancer, if you reduce the nutrients available in the tumors, the cells don't know what to do. Without the nutrients to grow, they enter a kind of crisis that leads to massive cell death.”
Yatrik M. Shah, Ph.D., senior author, Horace W. Davenport College Professor of Physiology at Michigan Medicine
Researchers found in cells and 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 proliferate. It is highly active in cancers with specific mutations and is known to cause cancer to become resistant to standard treatments. A low-protein diet, 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 in business. When a cell has a lot of 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 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 turn off mTORC.
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"We knew that nutrients were important for mTORC regulation, but we did not know how they directly signal mTORC. We discovered that nutrient signaling is just as important for regulating mTORC as oncogenic signaling," said study lead author Sumeet Solanki. Ph.D., a research investigator at the Rogel Cancer Center.
The researchers confirmed their findings in cells and mice, where they saw that limiting amino acids stopped cancer growth and led to increased cell death. They also examined tissue biopsies from patients with colon cancer, which confirmed that high mTORC markers correlated with higher resistance to chemotherapy and worse outcomes. Solanki said this could provide an opportunity to directly treat patients with this marker.
"A low-protein diet is not a stand-alone treatment. It needs to be combined with something else, such as chemotherapy," Solanki said.
The risk with a low-protein diet is that people with cancer often experience muscle weakness and weight loss, which limiting protein could worsen.
"Putting cancer patients on a low-protein diet long-term is not ideal. But if you can find key times - like at the start of chemotherapy or radiation - when patients could be on a low-protein diet for a week or two, then we think that could potentially increase the effectiveness of these treatments," Shah said.
Further research will refine this concept of a therapeutic window for limiting amino acids. Researchers will also try to understand how these pathways generate resistance to treatment and whether an inhibitor could block GATOR complexes.
Source:
Reference:
Solanki, S., et al. (2022) Dysregulated amino acid recognition drives colon cancer growth and metabolic reprogramming, leading to chemoresistance. Gastroenterology. doi.org/10.1053/j.gastro.2022.11.014.
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