Researchers rein in cancer cells

Controlling the level of telomerase can probably prevent cancer metastasis

Researchers have found the mechanism by which controlling the levels of telomerase can help in reining in the growth of cancer cells and probably prevent cancer metastasis.

Unlike normal cells, most cancer cells have high levels of telomerase and this leads to more than normal length of the telomere. Telomeres protect chromosome ends somewhat like the plastic clips at the end of shoelaces that prevent fraying of the ends. While cells die when the telomere becomes shorter beyond a certain limit, in the case of cancer cells the length of the telomere is maintained thereby ensuring extended life span of the cells.

In normal cells the telomerase is kept under tight control. But in about 85% of all cancers the telomerase levels are more than normal leading to malignant transformation and aggressive metastasis in many cases. “It is not clearly understood how telomerase is kept under tight control in normal cells and how the telomerase levels gets increased in cancerous cells,” says the  author of the paper.

It is already known that when the amount of a particular protein that suppresses the spread of cancer (metastasis) called non-metastatic 2 (NME2) is high the tendency of the cancer to spread is low. But what came as a surprise is the role of this protein in controlling the telomerase levels as well. “How NME2 controls metastasis is not clearly understood. But surprisingly we found that NME2 controls the levels of telomerase,” Dr.  says.

The mechanism

The researchers found that NME2 binds to a DNA structure (G-quadrauplex) found in the telomerase promoter. Once bound, the NME2 facilitates a well known suppressor of gene expression (REST complex) to bind to the telomerase promoter and control the production of telomerase.

“Experiments show that if you don’t have NME2 then the REST suppressor cannot bind to the telomerase promoter and control the production of telomerase,” says one of the authors of the paper.

“We used proteomics approach to study the protein-protein interactions. We could identify protein members of the REST complex that interact with NME2. The IGIB team then confirmed the role of the REST complex and its function,” says a co-author of the paper.

Drug target
“We established that the DNA structure (G-quadrauplex) could be a possible drug target once we understood the mechanism of NME2 binding to the promoter followed by the REST suppressor complex,” Dr. says. The involvement of a DNA structural architecture allowed the team to use small molecules that recognised the specific structure.

Since the amount of NME2 is low in many metastatic cancerous cells, the researchers used small molecules that were able to function like NME2 by recognising and binding to the DNA structure. “We screened 20 molecules and 11 were able to bring down the telomerase level in fibrosarcoma cancer cells,” Dr. says.

Based on the initial lead from the small molecules, the researchers are planning to synthesise new molecules to optimise for drug-like characteristics for therapeutic use. The molecules will then be tested on animals.

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