Critical Pathway in Cell Cycle May Lead to Cancer Development
A team of scientists at the Salk Institute for Biological Studies has identified why disruption of a vital pathway in cell cycle control leads to the proliferation of cancer cells. Their findings on telomeres, published today in Molecular Cell, suggest a potential target for preventive measures against cancer, aging, and other diseases.
Telomeres are crucial to DNA replication, tumor suppression, and aging. "As telomeres shorten during normal [cellular] aging, they activate a DNA damage response to arrest cell growth, which protects our DNA from harm," said senior study author Jan Karlseder, PhD, Professor in the Molecular and Cell Biology Laboratory at the Salk Institute. Shortened telomeres have been identified in pancreatic, bone, prostate, bladder, lung, kidney, and head and neck cancers
Dr. Karlseder and his team identified that cell growth arrest due to shortening telomeres is confined to one specific portion of the cell cycle, called the G1 phase, which is the most protected stage of the cell cycle. "The pathway controlling G1-phase growth arrest, however, is commonly altered in cancer cells, allowing cancer cells to divide despite shortened telomeres, which can lead to the genomic instability seen in malignant cells,” Dr. Karlseder said.
Study Details
In the study, Dr. Karlseder and colleagues mimicked the process of cellular aging by partially removing the TRF2 protein from the telomeres of human fibrosarcoma cells. By doing so, they were able to experimentally reproduce the process that occurs naturally as cells age. This telomere deprotection exposed the ends of chromosomes during certain stages of the cell cycle. In this state, they found that telomeres exhibited a partial DNA damage response: The ends of chromosomes were protected against fusing and fraying, but cell growth was still arrested.
"Basically, there's cell growth arrest without genomic instability,” said lead author Anthony Cesare, PhD, a research associate in Dr. Karlseder's laboratory. “Thus, telomere aging, in normal, healthy cells and living organisms, means cell arrest, but no harmful genetic effects."
p53 Pathway Plays Key Role
The investigators identified the p53 pathway, a molecular mechanism that normally protects a cell's genetic material and suppresses tumors, as the key player in the response to telomere deprotection. When cells lose the function of p53, they can no longer arrest cells in the G1 phase, an important point in the cell cycle for repairing DNA damage or, if the damage cannot be repaired, targeting the cell for programmed death.
Because telomere deprotection results in a partial DNA damage response that only arrests cells in G1 through the p53 pathway, once cells lose p53 function telomere deprotection no longer arrests growth. "Cells without functional p53 are able to divide with deprotected telomeres, which causes genomic instability," said Dr. Karlseder.
According to the researchers, better understanding of the telomere shortening process may lead to the ability to influence cellular aging and, as a result, stunt cancer cell growth. They say the next step is determining why this deprotection response is muted in cancer cells, and possibly affecting this process to prevent cancer cells from growing.
The study was supported by the National Institutes of Health, the John Sabo Trust, the Highland Street Foundation, the Human Frontier Science Program, the Japan Society for the Promotion of Science, and the Salk Institute Glenn Center for Aging.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
