The "lifeline" of 30% colorectal cancer cells is an amino acid

Colorectal cancer is one of the most common cancer types in China, with more than 3 million new cases every year In recent years, the incidence of colorectal cancer has shown a trend of youth, which has become a public health problem that needs to be addressed Recently, scientists from research institutions in China and the United States, such as Case Western Reserve University and the Third Military Medical University, found that quite a part of colon cancer has a special "hobby" for glutamine, which is higher than the demand of other cells However, hobbies often become a person's weakness and even a "lifeline", the same for cancer cells The researchers believe that this weakness of cancer cells may become the next effective drug target for colorectal cancer treatment This achievement was published in the recent Nature journal Nature communications
▲ glutamine structure It turns out that this kind of colon cancer cells which have a special preference for glutamine have PIK3CA gene mutations, the latter widely exists in many types of tumors, including about 30% of colon cancer cells The gene encodes P110 α, a catalytic subunit of phosphatidylinositol 3-kinase (P13K) P13K plays an important role in cell proliferation, survival and metastasis Once activated, P13K can activate PI3K Akt and other classical signaling pathways, which has a wide range of effects on cells This mutant P110 α will eventually lead to a significant increase in gpt2 expression, and glutamine is the substrate of gpt2
▲ schematic diagram of tricarboxylic acid cycle In fact, glutamine has an extraordinary significance for cancer cells Unlike normal cells, the glucose absorbed by cancer cells is mainly decomposed into lactic acid through glycolysis to generate energy, even in the presence of oxygen On the other hand, glutamine is often the starting point of TCA cycle in cancer cells It needs to be converted into α - ketoglutarate (α kg) by three enzymes including GPT, and then officially enter TCA cycle In the cancer cells with PIK3CA gene mutation, due to the abnormal increase of gpt2 activity, the demand for glutamine is also greatly increased, which has become the "lifeline" of these cancer cells When researchers stopped supplying glutamine to cancer cells in vitro with mutations in the PIK3CA gene, the cancer cells would not survive the "test" and die, while cancer cells without the mutation would not be affected Moreover, when the researchers injected the colorectal cancer model with the PIK3CA gene mutation with aminoxyacetate, the tumor growth was inhibited Aminoacetic acid is a small molecule inhibitor of many transaminases including gpt2
Structure of aminoacetic acid "We will start clinical trials of colorectal cancer at the university hospitals Seidman cancer center this summer based on this finding," said Neal Meropol, one of the authors of the article and professor of the Seidman cancer center In this clinical trial, led by him, the researchers will test the efficacy of a glutamate metabolism inhibitor in patients with advanced colorectal cancer.