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Researchers from the University of Michigan Rogel Cancer Center have published recent research within the journal Gastroenterology, showing that a low-protein weight loss program disrupts a nutrient signaling pathways in cells that could be a driver of colon cancer.
The research focused on some of the essential cellular nutrient sensing molecule called mTORC1. This molecule allows cells to sense different nutrients to permit them to grow and proliferate. But when nutrients are limited, cells dial down nutrient sensing cascade and switch off mTORC1.
mTORC1 can be known to be highly energetic in colon—and other cancers— and is understood to cause cancer to turn into resistant to straightforward treatments, so the investigators sought to find whether colon tumors hijack nutrient sensing pathways to fireplace up mTORC1.
“In colon cancer, once you decrease the nutrients available within the tumors, the cells don’t know what to do,” said Yatrik M. Shah, PhD, professor of Physiology at Michigan Medicine and senior writer on the paper. “Without the nutrients to grow, they undergo a type of crisis, which ends up in massive cell death.”
Of particular interest to the team was how the GTPase activity towards Rags (GATOR), which works with mTORC1 to maintain it functional, modified the dietary signals inside cells. GATOR2 has been shown to activate mTORC1 when cells have an abundance of nutrients, while GATOR1 deactivates mTORC1 when nutrients are low.
Because of this, mTORC1 has been targeted by potential cancer therapies which have sought to dam its cancer-causing signals. This approach, nevertheless, comes with significant side-effects, and when patients stop taking therapies that block mTORC1, their cancer reemerges.
The University of Michigan team sought a distinct approach to regulating cell growth by identifying lack of function mutations of the GATOR1 complex that altered expression of amino acid sensing pathways which are predictive of poor patient outcomes.
“We show that dysregulated amino acid sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models,” the researcher wrote. “We found amino acid sensing pathways to be essential within the cellular reprogramming of chemoresistance, and chemotherapeutic resistant colon cancer patients exhibited deregulated amino acid sensing.”
This finding suggested that blocking the nutrient pathway by limiting amino acids through a low-protein weight loss program offers another solution to shut down mTORC.
“We knew that nutrients were essential in mTORC regulation, but we didn’t know the way they directly signal to mTORC. We discovered the nutrient signaling pathway is just as essential to manage mTORC because the oncogenic signaling pathway,” said first writer Sumeet Solanki, PhD, a research investigator on the Rogel Cancer Center.
Researchers confirmed their findings in cell and mouse models, demonstrating that limiting amino acids stopped the cancer from growing and led to increased cell death. The team examined tissue biopsies from patients with colon cancer, which confirmed high markers of mTORC correlated with more resistance to chemotherapy and worse outcomes. Solanki noted that this might provide a chance to direct treatment for patients with this biomarker.
“A low-protein weight loss program won’t be standalone treatment. It needs to be combined with something else, reminiscent of chemotherapy,” Solanki said.
The researchers noted that putting patients on a long-term, low-protein weight loss program has its own complications, including muscle weakness and weight reduction, already an issue with many cancer patients. As a substitute, the team hopes to further refine its research to discover a more limited therapeutic window when doing this to limit amino acids will probably be more useful in obstructing tumor development.
Additional studies may also seek to know how these pathways are creating resistance to treatment and whether an inhibitor could block the GATOR complexes.