1 September 2008

Key cancer growth enzyme decoded

Agence France-Presse
The code that controls a key enzyme in the growth of most cancers has finally been cracked by researchers, opening a new path to a new class of anti-cancer drugs.
Telomerase RNA

Cancer catalyst: Three-dimensional structure of the conserved pseudoknot found in human telomerase RNA. Credit: Juli Feigon/University of California at Los Angeles

PARIS: The code that controls a key enzyme in the growth of most cancers has finally been cracked by researchers, opening a new path to a new class of anti-cancer drugs.

Scientists who reviewed the study but were not involved in the work hailed it as a breakthrough in fundamental cancer biology, but cautioned that much work remained before theexploit could be translated into next-generation therapies.

Ideal chemotherapy target

The enzyme, known as telomerase, “is an ideal target for chemotherapy because it is active in almost all human cancer tumours, but inactive in most normal cells,” said Emmanuel Skordalakes, a professor at the Wistar Institute in Philadelphia, USA, who led the study.

“That means that a drug that deactivates telomerase would likely work against all cancers, with few side effects,” he added.

In humans, telomerase adds short sequences of DNA known as telomeres to the ends of chromosomes, thus preventing damage and the loss of genetic information when cells divide. The enzyme is active mainly in cells that multiply frequently, such as embryonic stem cells, but is switched off in normal adult cells to avoid problems caused by runaway cell proliferation.

In cancer cells, however, telomerase is activated, allowing the disease cells to replicate endlessly and achieve what scientists call ‘cellular immortality’, the hallmark of all cancers.

A decade-long search for telomerase inhibitors has, up until now, been hampered by a lack of knowledge of how the enzyme is structured. Skordalakes and his colleagues are the first to provide a complete view of a critically important protein within the telomerase molecule.

Critical to development

It reveals, at an atomic level, how the enzyme replicates the tips of chromosomes, a process critical to the development of tumours.

The breakdown of this same mechanism is also involved in the ageing process, which means any new inhibitor drugs might also help boost longevity.

The main obstacle blocking research on the complicated architecture of telomerase was simply gathering a sufficient quantity of the enzyme. Neither humans nor yeast – the standard laboratory sources – yielded enough.

Skordalakes screened a wide range of organisms, including protozoa and insects, before discovering that the red flour beetle produced copious amounts of telomerase in a stable form.

Find dubbed ‘a breathrough’

“This was really the breakthrough,” he said. “Once we found that the gene from this organism expressed the protein in the quantities we needed, we were able to move quickly.”

The researchers used a technique called X-ray crystallography that analyses the patterns of X-rays beamed at molecule crystals to create a three-dimensional structure of the enzyme’s active region.
Knowing how this region – called the telomerase reverse transcriptase protein (TERT) – is structured made it possible to decipher how the enzyme works.

“For the first time, we can see how telomerase assembles at the end of chromosomes in initiate telomere replication,” said Skordalakes.

Several scientists who reviewed the study ahead of publication hailed its significance. They added, though, that it was only one in a series of essential steps that led to any novel treatment for cancer.

“There is no doubt that having determined the structure of telomerase is extremely important in understanding cancer biology, and will probably help lead us in the development of telomerase inhibitors,” said Herbie Newell, head of Britain’s Translational Research at Cancer Research.

“But whether these inhibitors will ultimately represent an effective class of anti-cancer treatments, it is too early to say,” he added.

Jon Wilson, a scientist at the Institute of Cancer Research in London, described the research as a “major breakthrough” in the study of telomeres in the cancer process.

But he, too, cautioned that the development of drugs to deactivate the enzyme “in a therapeutic setting, although an exciting prospect, will require a great deal more research.”

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