Researchers at UT Southwestern Medical Center have found that alternative splicing -- a process that allows a single gene to code for multiple proteins -- appears to be a new potential target for anti-telomerase cancer therapy.
The enzyme telomerase is overexpressed in almost all cancer cells, and previous research efforts have failed to identify good telomerase inhibitors. The study by Dr. Woodring Wright and UT Southwestern colleagues in the April 4 issue of Cell Reports identifies a new approach for inhibiting telomerase, which is an enzyme that drives uncontrolled division and replication of cancer cells.
Alternative splicing allows genetic information to be assembled in different ways and is almost always controlled by DNA sequences that are immediately adjacent to the parts of a gene that code for protein. "In the case of the telomerase gene, we found that these controlling regions are located very far from the protein coding regions and that they contain unusual DNA sequences," said Dr. Wright, professor of cell biology and internal medicine. "Their unusual DNA structure suggests that humans regulate telomerase in a very different fashion that we may be able to exploit to develop inhibitors of the enzyme."
Most of the splice variants that telomerase makes are inactive, but Dr. Wright's team demonstrated that it was possible to shift the splicing to make even less active telomerase, potentially providing a new approach for cancer therapy.
Telomeres are specialized structures at the ends of each chromosome. As DNA replicates, telomeres shorten each time a cell divides. Telomerase in human cancer cells is 10 to 20 times more active than in normal body cells. The increase provides a selective growth advantage to many types of tumors. If telomerase activity was to be turned off, then telomeres in cancer cells would shorten like they do in normal body cells.
"The oft-used analogy is that telomeres are like the plastic ends of shoelaces that protect them from fraying," Dr. Wright said. "Once the plastic becomes damaged and falls off, the shoelace can no longer be threaded effectively. The only solution at that point is to throw the shoelace away."
In most tissues, telomerase turns off during development, after which telomeres shorten and limit the number of times a cell can divide, eventually losing their capping function similar to the shoelace tip falling off. This timing also functions as a tumor-protection mechanism, since the limited cellular lifespan prevents pre-malignant cells from accumulating the mutations they need to become cancerous.
Preclinical studies have shown that inhibiting telomerase causes tumor cells to lose immortality, re-initiate telomere shortening, and eventually die. In the event that a tumor has already thoroughly developed, it may be surgically removed, and following conventional chemotherapy, telomerase inhibition could prevent rare surviving cells from having enough divisions to cause a relapse.
Dr. Wright said the alternative splicing method also could be useful for regenerative medicine, because telomeres in our stem cells shorten with age and that eventually compromises their function. "Under the right circumstances, increasing or decreasing telomerase activity could profoundly affect our treatments for both cancer and aging," he said.
- Mandy S. Wong, Ling Chen, Christopher Foster, Radhika Kainthla, Jerry W. Shay, Woodring E. Wright. Regulation of Telomerase Alternative Splicing: A Target for Chemotherapy. Cell Reports, 2013; DOI: 10.1016/j.celrep.2013.03.011
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