BioWorld International Correspondent

LONDON - The identification of a previously unknown metabolic pathway in cancer cells could ultimately lead to new targets for anticancer drugs, researchers predict.

A team from the University of Glasgow in Scotland, collaborating with scientists at the Fred Hutchinson Cancer Research Center in Seattle, has shown that the molecule c-Myc plays a crucial role in the synthesis of molecules a cell needs to make more proteins. The finding helps to explain how cells in many tumors manage to multiply so rapidly.

Robert White, professor of gene transcription at the University of Glasgow, told BioWorld International, "It was well known that many types of cancer make too much c-Myc and that c-Myc makes cells grow too fast, but it was not clear how this happened. Identifying this unexpected pathway that is very likely to be involved in the formation of cancer, suggests potential new targets for therapeutic intervention in the long term."

The team's finding is reported in the Jan. 16, 2003, issue of Nature in an article titled "Direct activation of RNA polymerase III transcription by c-Myc."

Sir Paul Nurse, CEO of Cancer Research UK, which helped to fund the work, said, "We have long suspected that c-Myc was one of the key molecules responsible for driving cell growth but we've lacked evidence about how the molecule worked and that's left us powerless to develop therapies to intervene.

"This new study is extremely important. It fills a big hole in our understanding of cancer on the molecular level and gives us a promising new angle of attack for future treatments."

White's laboratory studies the RNA polymerase known as pol III, a molecule responsible for transcribing about 10 percent of all genes, including a set of genes that encode the information for several small molecules, including transfer RNA and 5S ribosomal RNA. The latter two molecules are essential for biosynthesis of proteins and, ultimately, for cell growth. In cancer cells, levels of transcription of pol III - and thus of transfer RNA and 5S ribosomal RNA - are high, and many researchers believe that the characteristic contributes to their ability to grow quickly.

In 1999, White met Robert Eisenman of the Fred Hutchinson Cancer Research Center (one of the co-authors of the Nature paper), who is one of the world's leading authorities on c-Myc. The researchers decided to collaborate on a study to determine whether the high levels of c-Myc in cancer cells are related to the high levels of pol III transcription in cancer cells.

"We found, as the Nature paper explains, that c-Myc has a profound effect on pol III transcriptional activity," White said. "In cells in which levels of c-Myc have been abnormally elevated, you see a dramatic increase in the synthesis of small molecules, such as transfer RNA and 5S ribosomal RNA. This means we have identified a new set of genetic targets for c-Myc and a novel mechanism that c-Myc uses in cells that may well explain its ability to drive abnormal rates of growth in cancer cells."

Experiments carried out by White's student, Nati Gomez, also showed that when c-Myc was removed from cells, levels of pol III transcription were reduced. The team showed that c-Myc could bind directly to the genes that encode transfer RNA and 5S ribosomal RNA and that its ability to find its way onto those genes is probably mediated by protein-protein interactions with a molecule already known to be a pol III transcription factor. That molecule is called transcription factor IIIB.

White said he and his colleagues will continue to study the role of c-Myc in controlling the transcription of pol III, including working out the detailed nature of the molecular interactions involved.

"We are also looking at whether c-Myc regulates another cellular RNA polymerase called pol I," he said. "There are good reasons for thinking that it does."