A low-protein diet can starve cancer cells and overcome resistance to treatment

Cancer cells need nutrients to survive and grow
.
One of the most important nutrient-sensing molecules in cells is called mTORC1
.
It is often referred to as the master regulator of cell growth, enabling cells to sense different nutrients and thus grow and proliferate
.
When nutrients are limited, cells turn down the nutrient induction cascade and turn off mTORC1
.

While mTORC1 is known to be highly active in colon cancer, the key question is whether colon tumors hijack nutrient sensing pathways to activate master regulators
.

"In colon cancer, when you reduce the nutrients available in the tumor, the cells don't know what to do
.
Without the nutrients they need to grow, they go through a kind of crisis that leads to massive cell death," said senior author Yatrik M.
Shah, Ph.
D.
, professor of physiology at Horace W.
Davenport College of
Michigan Medical College.

Researchers found in cells and mice that low-protein diets blocked nutrient signaling pathways that activate major regulators of cancer growth.

This regulator, called mTORC1, controls how cells use nutrient signals to grow and reproduce
.
It is highly active in cancers with specific mutations and is known to cause cancer to develop resistance to standard treatments
.
The low-protein diet, specifically the reduction of two key amino acids, altered the nutrient signal
through a complex called GATOR.

GATOR1 and GATOR2 work together to keep mTORC1 up and running
.
When cells have sufficient nutrients, GATOR2 activates mTORC1
.
When nutriently deficient, GATOR1 inactivates
mTORC1.
Restricting certain amino acids blocks this nutrient signal
.

Previous inhibition of mTORC has focused on inhibiting its carcinogenic
signaling.
But these inhibitors have significant side effects — when patients stop taking them, the cancer comes back
.
The study suggests that blocking nutritional pathways by restricting amino acids on a low-protein diet is another way
to turn off mTORC.

"We know that nutrients are important in mTORC regulation, but we don't know how they signal directly to mTORC
.
We found that nutrient signaling pathways are as important for regulating mTORC as they are for oncogenic signaling pathways," said Sumeet Solanki, Ph.
D.
, first author of the study and a researcher at
the Rogel Cancer Center.

The researchers confirmed their findings in cells and mice, where they saw that restricted amino acids prevented cancer growth and led to increased
cell death.
They also looked at tissue biopsies from colon cancer patients, and the results confirmed that high labeling of mTRC was associated with
more chemotherapy resistance and worse outcomes.
Solanki said this could provide an opportunity
for patients with this marker to guide treatment.

"Low-protein diets are not a stand-alone treatment
.
It has to be combined with other things, like chemotherapy," Solanki said
.
The risk of a low-protein diet is that cancer patients often experience muscle weakness and weight loss, which may be exacerbated by limiting protein intake
.
"Giving cancer patients a protein-deficient diet for a long time is not ideal
.
But if you can find a critical window period, such as at the start of chemotherapy or radiation therapy, where patients can go on a low-protein diet for one to two weeks, we have the potential to improve the efficacy
of these treatments.
Shah said
.

Further research will refine the concept of
a therapeutic window that limits amino acids.
The researchers will also try to understand how these pathways become resistant to treatment and whether there is an inhibitor that blocks the GATOR complex
.

Dysregulated amino acid sensing drives colorectal cancer growth and metabolic reprogramming leading to chemoresistance