Detailed study of how cancer cells avoid death from starvation and chemotherapy

Chemotherapy has been successful in treating cancer and extending patients' lives, but because cancer cells rewire the process by which they convert fuel into energy (metabolism) to counteract the effects of the drugs. , it is known that it does not have a long-lasting effect on everyone. Many of these drugs are so-called antimetabolites, which interfere with cellular processes necessary for tumor growth and survival.

The three drugs used in this study (raltitrexed, N-(phosphoacetyl)-1-aspartic acid (PALA), and brequinar) were used to treat cancer cells with pyrimidines, molecules that are essential components of the genetic character code. or nucleotides). , constitutes RNA and DNA. Cancer cells have access to sources of pyrimidines to produce more cancer cells and to produce uridine nucleotides, which are the main fuel source as cancer cells rapidly reproduce, grow, and die. Must be. Disrupting the fast-paced but fragile pyrimidine synthesis pathway, as some chemotherapies are designed to do, can starve cancer cells rapidly and lead to spontaneous cell death (apoptosis). there is.

The new study, led by researchers at New York University Langone Health and its Perlmutter Cancer Center, shows that a sustained lack of energy from glucose (the chemical term for blood sugar) needed to fuel tumor growth. It shows how cancer cells survive in a hostile environment. Researchers hope that if they can better understand how cancer cells evade the drugs' attempts to kill them in a low-glucose environment, they will be able to develop better or more effective combination therapies. It is said that this may lead to the design of

Publication in magazines natural metabolism The study results showed that the low-glucose environment that cancer cells live in, the tumor microenvironment, slows the consumption of cancer cells' existing uridine nucleotide stores, making chemotherapy less effective.

Normally, uridine nucleotides are produced and consumed to help create the genetic character code and cell metabolism. However, when DNA and RNA construction is inhibited by these chemotherapies, glucose is required to convert one form of uridine, UTP, to another available form, UDP-glucose. The researchers found that consumption of the uridine nucleotide pool was similar. Ironically, the low-glucose tumor microenvironment appears to slow the consumption of uridine nucleotides by cells, possibly slowing the rate of cell death, the researchers said. Researchers say cancer cells need to run out of pyrimidine building blocks, including uridine nucleotides, before they self-destruct.

In other experiments, the low-glucose tumor microenvironment also failed to activate BAX and BAK, two proteins found on the surface of mitochondria, the cells' fuel generators. When activated, these trigger proteins instantly turn on a series of caspase enzymes that help mitochondria collapse and initiate apoptosis (cell death).

“Our research explores 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 it's being suppressed,” said lead researcher Dr. Min-woo Nam, a postdoctoral fellow in the university's Department of Pathology. New York University Grossman School of Medicine and Perlmutter Cancer Center.

“Our results illustrate what was previously unknown about how metabolic changes in the tumor microenvironment affect chemotherapy. Low glucose promotes cancer cell proliferation. “It slows down the consumption and depletion of the uridine nucleotides required for cancer cells, and prevents the resulting apoptosis, or death, of cancer cells,'' said senior researcher Dr. Richard Possemato. Possemart is an associate professor in the Department of Pathology at New York University Grossman School of Medicine and a member of the Perlmutter Cancer Center.

Possemaert, who also co-leads Perlmutter University's cancer cell biology program, said his team's findings could one day be used to change or trick cancer cells into doing the same thing in a low-glucose microenvironment. He says that it may be used to develop chemotherapy or combination therapy that responds to cancer. They will be present in an otherwise stable glucose microenvironment.

He also developed diagnostic tests to measure how a patient's cancer cells are likely to respond to a low glucose microenvironment and predict how well a patient will respond to a particular chemotherapy. He also says that it is possible.

Possemart said his team plans to investigate how blocking other cancer cell pathways triggers apoptosis in response to these chemotherapy treatments. Several drugs already exist that may be able to accomplish this, such as Chk-1 and ATR inhibitors, but Chk-1 and ATR inhibitors are poorly tolerated by patients and require further study. He points out that there is a need.

For the study, researchers conducted a scan of 3,000 cancer cell genes known to be involved in cell metabolism, and found that deletions of genes necessary for cancer cell survival after chemotherapy were detected. Identified. Most of the genes they discovered that are essential for cell survival in a low-glucose tumor environment were also involved in pyrimidine synthesis, a precise biological pathway that is the target of many chemotherapy treatments. This is an experiment to see how different clones of cancer cells grown in the lab respond to hypoglycemia after chemotherapy, and what other chemical processes are affected by low blood sugar levels. focused on.

Funding for this research was provided by National Institutes of Health grants P30CA016087, R01CA286141, R01CA214948, R01GM132491, and R35GM139610. Additional financial support was provided by the Pew Charitable Trusts, the Alexander and Margaret Stewart Trust, and the American Cancer Society.

In addition to Nam and Possemato, other NYU Langone researchers involved in the study include co-investigators Wenxin Xia, Abdul Hannan Mir, and Tony Huang.