Researchers Find That a Silent Gene Mutation can Change the Function of an Anticancer Drug Pump
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According to a study conducted at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), a genetic mutation that does not cause a change in the amino acid sequence of the resulting protein can still alter the protein's expected function.
The study shows that mutations involving only single chemical bases in a gene known as the multidrug resistance gene (MDR1) that do not affect the protein sequence of the MDR1 gene product can still alter the protein's ability to bind certain drugs.
Changes in drug binding may ultimately affect the response to treatment with many types of drugs, including those used in chemotherapy. The results of this study appear online in Science Express on December 21, 2006.
The genetic mutations examined in this research are known as single nucleotide polymorphisms (SNPs) and are very common. Some SNPs do not change the DNA's coding sequence, so these types of so-called 'silent' mutations were not thought to change the function of the resulting proteins.
"This study provides an exception to the silent SNP paradigm by showing that some minor mutations can profoundly affect normal cell activity," said NCI Director John E. Niederhuber, M.D.
"These results may not only change our thinking about mechanisms of drug resistance, but may also cause us to reassess our whole understanding of SNPs in general, and what role they play in disease."
Despite success in treating some cancers with chemotherapy, many tumors are naturally resistant to anticancer drugs or become resistant to chemotherapy after many rounds of treatment.
Researchers at NCI and elsewhere have discovered one way that cancer cells become resistant to anticancer drugs: they expel drug molecules using pumps embedded in the cellular membrane.
One of these pumps, called P-glycoprotein (P-gp), is the protein product of the MDR1 gene and contributes to drug resistance in about 50 percent of human cancers.
P-gp prevents the accumulation of powerful anticancer drugs, such as etoposide and Taxol, in tumor cells.
The same pump is also involved in determining how many different drugs, including anticancer drugs, are taken up or expelled from the cell.
In this study, researchers led by Michael M. Gottesman, M.D., head of the Laboratory of Cell Biology within NCI's Center for Cancer Research, demonstrated that SNPs in the MDR1 gene result in a pump with an altered ability to interact with certain drugs and pump inhibitor molecules.
"We think that this SNP affected protein function because it forced the cell to read a different DNA codon than it usually does," said Gottesman.
"While the same exact protein sequence eventually got made, this slight change might slow the folding rhythm, resulting in an altered protein conformation, which in turn affects function."
Since silent SNPs are frequently found in nature, their biological role has largely been overlooked. However, this study raises the possibility that even silent mutations could contribute to the development of cancer and many other diseases.
