GLucose is the fuel for the cellular engine. It enhances cellular functions and serves as a raw material for the synthesis of a variety of essential biomolecules, including the sugar backbones of DNA and RNA. This is very important for the growth and proliferation of all cells in the body, including cancer cells. However, cancer cells proliferate despite their surrounding environment. tumor microenvironment– Significant glucose depletion.1
In a new study published today (November 26th), natural metabolismresearchers at New York University’s Grossman School of Medicine found that in the presence of certain chemotherapy drugs, cancer cells can rewire their metabolism to take advantage of the glucose-depleted tumor microenvironment and escape death. I reported that it was possible.2
“Our research shows how cancer cells offset the effects of a low-glucose tumor microenvironment and how these changes in cancer cell metabolism may minimize the effects of chemotherapy. “It shows that we are holding back,” he said. Richard PossemartCancer biologist and co-author of the paper, press release.
A better understanding of the influence of the tumor microenvironment on cancer cell proliferation and survival will guide the development of targeted therapies and help predict response to drugs under specific conditions.
To grow rapidly, cancer cells need to rapidly manufacture DNA and RNA, which requires sufficient amounts of purines and pyrimidines. Analyzing the levels of 3,000 genes in T-cell leukemia cell lines grown on high or low levels of glucose, Possemat and his team found that genes involved in pyrimidine synthesis were significantly reduced in cells grown in a low-glucose environment. We observed that the expression level was low. The researchers were surprised to find that the cells grew at similar rates in both glucose conditions, suggesting that the cells used the same levels of nucleotides.
To understand this unexpected behavior, the authors pharmacologically inhibited pyrimidine synthesis in cancer cells growing in high glucose media. They observed that these cells were unable to proliferate and were stuck at the DNA replication stage. These cancer cells also express high levels of proteins that cause DNA breaks and cell death, ultimately rendering them unable to withstand treatment. However, when the researchers inhibited pyrimidine synthesis in cells grown in low-glucose medium, the cancer cells showed high rates of DNA synthesis and no signs of DNA breaks or cell death. When the inhibitor was washed away, these cells proliferated.
Despite the low glucose environment, cancer cell survival was selective for certain conditions. The cancer cells were saved from death only when the researchers administered chemotherapy drugs such as raltitrexed, a treatment for advanced colorectal cancer that works by inhibiting DNA replication. When drugs that damage DNA or target other steps in the nucleic acid replication process were applied, glucose restriction had no benefit and the cancer cells died.
Under normal conditions, a lack of pyrimidine causes cells to be unable to divide and eventually die. The authors hypothesized that low glucose levels may allow cancer cells to maintain a sufficient pool of pyrimidine, even though genes in the pyrimidine synthesis pathway are suppressed. Uridine triphosphate (UTP), a type of pyrimidine uridine, can be converted to other pyrimidines such as cytidine triphosphate (CTP). Via an alternative pathway, cells can also use UTP to produce uridine diphosphate (UDP)-glucose, an essential component of glycogen production and other biochemical processes. Possemato and his team observed that in the presence of high glucose and pyrimidine synthesis inhibitors, cells directed UTP rather than CTP to synthesize UDP-glucose. However, under glucose limitation, UDP-glucose levels were observed to decrease, suggesting that cells conserve pyrimidine even when upstream enzymes are inhibited.
In addition to preserving the cellular pyrimidine pool, low glucose levels also prevent activation of the proteins Bcl-2-associated X protein (Bax) and the Bcl-2 antagonist killer 1 (Bak), which are important regulators of cell death. Ta. aisle. This ensured that cancer cells could survive in nutrient-poor environments.
“Our results illustrate what was previously unknown about how metabolic changes in the tumor microenvironment affect chemotherapy. Low glucose inhibits cancer cell proliferation. It slows down the consumption and depletion of the uridine nucleotides needed to promote apoptosis, or the resulting death of cancer cells,” Possemato said.
These findings could help develop chemotherapy that prevents cancer cells from growing in the low-glucose tumor microenvironment. It could also be useful in analyzing how a patient’s tumor responds to certain drugs when combined with glucose depletion strategies.
