‘Immortal’ enzyme may make cancer cells immune to therapy

School of Medicine researchers have shown that an enzyme that allows cancer cells to divide endlessly in the laboratory also may help them resist radiation and chemotherapy.

The study, published in a recent issue of the journal Oncogene, investigated how the enzyme telomerase, which often is produced by cancer cells, attaches to chromosomes.

Surprisingly, the findings also revealed that the enzyme might reduce the effectiveness of cancer therapy.

“These results provide a much better understanding of telomerase and have important implications for cancer therapy,” said lead investigator Tej K. Pandita, Ph.D., assistant professor of radiation oncology. “This suggests that the use of drugs to inhibit or inactivate telomerase might improve the effectiveness of cancer therapy.”

According to Pandita, several telomerase-inhibiting drugs are under development.

Under normal conditions, telomerase is produced mainly by stem cells and by egg and sperm cells and their progenitors, where it adds repeating segments of DNA to the ends of chromosomes.

These ends, known as telomeres, protect the chromosome’s tips. In addition, they are believed to serve as a cell’s biological clock. Each time a cell divides, the telomeres on its chromosomes become shorter. When they drop to a certain length, the cell stops dividing and gradually dies.

Telomerase also is found in more than 80 percent of cancers. The enzyme helps cancer cells circumvent their biological clock by keeping their telomeres at a constant length, enabling the cells to divide indefinitely.

Pandita and his colleagues studied the gene for the catalytic subunit of human telomerase (the part of the telomerase molecule that binds to telomeres) in human cells.

To their surprise, they discovered that the joining of telomerase to the telomeres is followed some 60 hours later by an increase and decrease in the activity of dozens of genes, many of which are related to cancer progression and resistance to cancer therapy.

On one hand, it reduced that activity of genes involved in programmed cell death, which causes the demise of cells damaged by radiation chemotherapy and radiation therapy.

But it also increased the activity of genes involved in repairing damaged DNA. This triggered a greater increase in the repair of radiation-caused breaks in the DNA strand and removal of so-called DNA adducts, small molecules that damage DNA by clinging to it.

Since radiation therapy works by breaking DNA strands, and many types of chemotherapy work by causing DNA adducts, the researchers concluded that telomerase helps cancer cells survive many of our most potent forms of cancer therapy.

Pandita now is studying ways to block the binding of telomerase to telomeres.