Changing one's diet may be necessary to improve colon cancer treatment, according to a new study out of the University of Michigan Rogel Cancer Center. Cancer cells need nourishment to survive and thrive. mTORC1 is one of a cell's most important nutrient sensing molecules. It enables cells to sense a variety of nutrients and, as a result, to expand and multiply, so it is often referred to as the master regulator of cell growth. When nutrients are low, cells turn off mTORC1 and nutrient sensing is turned off.
The important question is whether colon malignancies use nutrient sensing pathways to turn on the master regulator, although mTORC1 is known to be hyperactive in colon cancer.
In colon cancer, when the amount of nutrients in the tumors decreases, the cells are confused about what to do. Without the nutrients needed to grow, they go into a crisis, causing significant cell death.
A low-protein diet has been shown by researchers to disrupt the nutritional signaling pathway that activates a key regulator of cancer growth in cells and mice.
The ability of cells to grow and proliferate in response to nutritional cues is governed by the regulator mTORC1. It is known to make cancer more resistant to conventional treatments and to be highly active in malignancies with specific mutations.
Through a complex called GATOR, a low-protein diet and more specifically the reduction of two essential amino acids altered the nutritional signals.
GATOR1 and GATOR2 together keep mTORC1 running. A cell's GATOR2 turns on mTORC1 when it has plenty of nutrients. Low nutrient levels cause GATOR1 to turn off mTORC1. By limiting certain amino acids, this nutritional signal is blocked.
Previous attempts to block mTORC have focused on blocking its cancer-causing signals. But when people stop taking these inhibitors, their negative effects return and the cancer comes back. Restricting amino acids with a low-protein diet offers an alternative method for inhibiting mTORC, according to the study.
“Although we are aware of the role that nutrients play in mTORC regulation, we were unsure how they directly communicate with mTORC. We found that both the oncogenic signaling pathway and the nutritional signaling pathway are crucial for controlling mTORC,” said Sumeet Solanki, a researcher at Rogel Cancer Center and first author of the study.
Limiting amino acids prevented the spread of cancer and increased cell death; this is supported by research in cells and mice. Additionally, they examined tissue biopsies from colon cancer patients and found that high mTORC indicators were associated with worse outcomes and increased chemoresistance. According to Solanki, this could offer a chance to tailor therapy for patients with this marker.
“A low-protein diet will not be the only way to cure it. It needs to be paired with another treatment, such as chemotherapy,” Solanki said.
A low-protein diet carries the danger of exacerbating the muscle weakness and weight loss that cancer patients often suffer from.
“Long-term protein restriction is not optimal for cancer patients. However, if there are certain times when patients can follow a low-protein diet for a week or two, such as the start of chemotherapy or radiation, we can increase the effectiveness of these treatments,” Shah added.
This therapeutic window concept for limiting amino acids will be developed with further studies. In addition, researchers will investigate whether an inhibitor can inhibit the formation of GATOR complexes and how these pathways lead to treatment resistance.
Source: University of Michigan