Monday, June 11, 2007

Cancer antidote in the attic

Researchers have discovered that “junk” RNA, which has the power to check unbridled cell growth, can help in developing anti-cancer treatments

A scientist born in India and his colleagues at Oxford seem to have unearthed an antidote to cancer from the “junkyards” of the human genome.

Aroul Ramadass and his associates in Alexandre Akoulitchev’s lab at Sir William Dunn School of Pathology, University of Oxford , have discovered RNA (ribonucleic acid) that is capable of stopping the runaway proliferation of cells. The amazing control that this particular RNA — whose role was previously unknown — showed of genes involved in cell division may lead to tools that can prevent the growth of tumour cells, the scientists hope. Their findings were published on January 21 in the online edition of the journal, Nature.

Cancer is a class of diseases characterised by uncontrolled cell division and the ability of these cells to invade tissues of neighbouring or faraway organs. Normally, unregulated growth is caused by damage to DNA, resulting in mutations in genes that encode for proteins controlling cell division. Thus, intervention at the genetic level could offer a lasting solution — present-day therapy revolves mainly around the destruction of malignant cells — feel experts.
Typically, RNA plays an important and direct role in the synthesis of proteins, the building blocks of our bodies. But the RNA that the Oxford scientists studied belongs to the type of RNA not directly involved in protein synthesis.

Significantly, the RNA was located in that part of the genome which scientists once considered “junk”. The Human Genome Project completed early this century found that some 34,000 genes, constituting just three per cent of the genome, are responsible for producing proteins. The rest of the genome does not seem to have any function. According to the latest estimates, this “junk” DNA produces around half a million varieties of RNA of unknown functions. And to be politically correct, scientists have of late dropped the word “junk” and are instead using “non-coding”, meaning the parts of the genome which do not encode for proteins useful to the host genome.

Explaining the mechanisms involved in the process, Ramadass said that the RNA molecule is capable of shutting down the gene dihydrofolate reductase (DHFR). The DHFR gene produces an enzyme that controls the production of thymine, one of the four bases of DNA. Thymine is necessary for cell multiplication.

“By slowing down the replication process, it prevents any ordinary cell from becoming cancerous,” Ramadass, who completed his master’s degree in molecular biology and biotechnology in 2000 from New Delhi ’s Indian Agricultural Research Institute, told KnowHow.
To demonstrate this, the scientists applied the technique “RNA silencing” which won two US scientists — Andrew Fire and Craig Mello — the 2006 Nobel Prize for physiology and medicine.
They specifically targeted the “interfering” RNA and nullified its effect on the DHFR gene. This, in turn, prevented the DHFR gene shutdown, leading to rapid cell multiplication.
“There’s been a quiet revolution taking place over the last few years regarding the role of RNA,” says Dr Alexandre Akoulitchev. “Scientists have begun to see ‘junk’ DNA as having a very important function. The variety of RNA types produced from this ‘junk’ is staggering and the functional implications are huge.”

Inhibiting the DHFR gene could help prevent the growth of neoplastic cancerous cells, ordinary cells which develop into tumour cells, such as in prostate cancer cells,” explains Dr Akoulitchev. “In fact, the first anti-cancer drug, Methotrexate, acts by binding and inhibiting the enzyme produced by this gene,” he says.

Interestingly, Methotrexate, the first-ever cancer drug to be approved by the US Food and Drug Administration in 1953, was designed and developed by the late Indian scientist, Yellapragada SubbaRow, who is often hailed as the “miracle man of miracle drugs”.
“This is not the first non-coding RNA originated from the non-coding part of the genome. But it is likely to be the first one to control the promoter (the gene that expresses the enzyme) in such a direct way,” Dr Akoulitchev told KnowHow.

Understanding how we can use the RNA to switch off or inhibit DHFR and other genes may help derive important therapeutic insights for developing new anti-cancer treatments, concludes the University of Oxford researcher

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