Glucose is the fuel to the cellular engine. It powers the cell’s functions and serves as the raw material for synthesizing various essential biomolecules, including the sugar backbone of DNA and RNA. It is crucial for the growth and proliferation of all cells in the body, including cancer cells. Yet, cancer cells thrive despite the fact that their surrounding environment—the tumor microenvironment—is severely depleted of glucose.1
In a new study published today (November 26) in Nature Metabolism, researchers at New York University Grossman School of Medicine reported that in the presence of certain chemotherapy drugs, cancer cells rewire their metabolisms to use a glucose-depleted tumor microenvironment to their advantage and escape death.2
“Our study shows how cancer cells manage to offset the impact of low-glucose tumor microenvironments, and how these changes in cancer cell metabolism minimize chemotherapy’s effectiveness,” said Richard Possemato, a cancer biologist and coauthor of the paper, in a press release.
The improved understanding of the tumor microenvironment’s impact on the growth and survival of cancer cells will help guide the development of targeted treatments and predict responses to drugs under specific conditions.
To multiply rapidly, cancer cells need to quickly manufacture DNA and RNA, which requires sufficient quantities of purines and pyrimidines. Upon analyzing the levels of 3,000 genes in a T cell leukemia cell line grown in high or low levels of glucose, Possemato and his team observed that genes involved in pyrimidine synthesis were expressed at lower levels in cells grown in the low-glucose environment. The researchers were surprised to find that the cells grew at similar rates in both glucose conditions, implying that they used the same levels of nucleotides.
To understand this unexpected behavior, the authors pharmacologically inhibited pyrimidine synthesis in cancer cells that were growing in a high-glucose medium. They observed that these cells were unable to proliferate and became stuck in the DNA replication phase. These cancer cells also expressed high levels of proteins that cause DNA breaks and cell death, leading them to eventually succumb to the treatment. However, when the researchers inhibited pyrimidine synthesis in cells grown in the low-glucose medium, the cancer cells showed high rates of DNA synthesis and no signs of DNA cleavage or cell death. Once the inhibitors were washed away, these cells proliferated.
The cancer cells’ survival despite a low-glucose environment was selective to specific conditions. The cancer cells escaped cell death only when the team exposed them to chemotherapy drugs like raltitrexed, a treatment for advanced bowel cancer that works by inhibiting DNA replication. When they applied drugs that damage DNA or target other steps of the nucleic acid replication process, glucose limitation was not an advantage, and the cancer cells died.
Under normal conditions, a cell that runs out of pyrimidines would not be able to divide and would eventually die. The authors hypothesized that despite the suppression of genes in the pyrimidine synthesis pathway, low-glucose levels help the cancer cells maintain sufficient pools of pyrimidine. Uridine triphosphate (UTP), a form of the pyrimidine uridine, can be converted into other pyrimidines like cytidine triphosphate (CTP). Via an alternate pathway, the cell can also use UTP to make 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 a pyrimidine synthesis inhibitor, the cells diverted UTP into the synthesis of UDP-glucose, rather than CTP. However, under glucose limitation, they observed lower levels of UDP-glucose, implying that the cells preserved pyrimidines upon inhibition of the upstream enzymes.
In addition to conservation of the cellular pyrimidine pool, low-glucose levels also prevented the activation of the proteins Bcl-2-associated X protein (Bax) and Bcl-2 antagonist killer 1 (Bak), which are crucial regulators of the cell death pathway. This ensured that the cancer cells survived the nutrient-deprived environment.
“Our results explain what has until now been unclear about how the altered metabolism of the tumor microenvironment impacts chemotherapy: low glucose slows down the consumption and exhaustion of uridine nucleotides needed to fuel cancer cell growth and hinders resulting apoptosis, or death, in cancer cells,” said Possemato in the press release.
These findings could aid the development of chemotherapy treatments that prevent cancer cells from thriving in low-glucose tumor microenvironments. They could also assist analyses of how patient tumors might respond to certain drugs when combined with glucose depletion strategies.
