Turning colon cancer cells around

Eighty-percent of colon cancers stem from a genetic mutation of the protein adenomatous polyposis coli, or APC. While the majority of people with that mutation will develop polyps, only some of the polyps will become cancerous, a phenomenon that is not fully understood. The research team decided to investigate non-genetic factors that could propel the disease, focusing their inquiry on the role of the amino acid glutamine.

"Cancer cells consume a great amount of glutamine to proliferate," said Molecular Biology and Biochemistry Associate Professor Mei Kong. "But we found that depriving them of glutamine doesn't kill all the tumor cells. Some tumor cells are able to adapt and in fact, when their glutamine supply runs low, they turn into a more invasive form of cancer."

The researchers found that a drop in cellular levels of the metabolite alpha-ketoglutarate after glutamine starvation accompanied the transition from benign to cancerous cells. This finding led them to conduct further investigation into the metabolite's role. When they provided a modified version of alpha-ketoglutarate to animal models with APC mutations, the results were significant. Just 23% of those given the modified metabolite developed rectal bleeding, an indication of intestinal tumors, compared to 90% of the animal models who did not receive it. It also curbed tumor growth and protected against disease-associated conditions such as weight loss.

"Supplementation of the modified alpha-ketoglutarate inhibits a key cancer-development signaling pathway in colon cancer cells, turning them into more normal cells," said researcher Thai Q. Tran, the paper's first author. "What's also notable is that we administered it by mixing it into drinking water, so it was easy to take and it did not affect overall health."

The research team would like to investigate further modification of the metabolite to specifically target colon cancer cells.

"We believe this new knowledge shows great potential for using less-toxic and natural approaches in combination with current therapies to more successfully treat colon cancer while better protecting patients' overall wellbeing," said Professor Kong.

The research was conducted in collaboration with Dr. Marian Waterman's group at UCI Medical School. Support for the research was provided by the National Institutes of Health and the American Cancer Society.

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Materials provided by University of California - Irvine. Note: Content may be edited for style and length.

Journal Reference:

1. Thai Q. Tran, Eric A. Hanse, Amber N. Habowski, Haiqing Li, Mari B. Ishak Gabra, Ying Yang, Xazmin H. Lowman, Amelia M. Ooi, Shu Y. Liao, Robert A. Edwards, Marian L. Waterman, Mei Kong. α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nature Cancer, 2020; 1 (3): 345 DOI: 10.1038/s43018-020-0035-5