Telomeres, telomerase play key roles
Conquest - Summer 2012
Blocking telomerase kills cancer cells, but opens new paths for disease progression
Understanding the “what” and “how” of telomerase may be critical in treating and eliminating cancer.
Telomerase is the enzyme that adds DNA sequence repeats (“TTAGGG” in all vertebrates) to the ends of telomere regions, thereby rescuing malignant cells from destruction in telomere crisis.
New research in mouse models with lymphoma shows that inhibiting telomerase kills tumor cells, but triggers resistant pathways that allow cancer to survive and spread.
“Telomerase is overexpressed in many advanced cancers, but assessing its potential as a therapeutic target requires us to understand what it does and how it does it,” says senior author Ronald DePinho, M.D., MD Anderson president.
In a series of experiments, the team found:
- Telomerase reactivation in malignant cells after genomic instability caused cancer progression.
- Inhibiting telomerase caused tumor cell death but also led to alternative lengthening of telomeres (ALT) independent of telomerase.
- ALT-positive cells increase both the expression and copy number of a gene called PGC-1ß, a key regulator of mitochondrial function, to compensate for mitochondrial defects and the high level of reactive oxygen species (ROS).
- Targeting PGC-1ß to weaken mitochondria function enhances anti-telomerase therapy.
“These findings allow us to anticipate how tumor cells might respond to telomerase inhibition and highlight the need to develop drug combinations that target telomerase and these adaptive resistance mechanisms,” DePinho says.
Reported in the Feb. 17, 2012, edition of Cell.
Telomere failure, telomerase activation
drive prostate cancer progression
Genomic instability caused by an erosion of the protective caps on chromosomes, followed by activation of an enzyme that reinforces those caps, allows malignant cells to evade destruction and acquire more deadly characteristics, according to
MD Anderson researchers.
The research focused on telomeres. Telomerase is inactive in normal cells. In cancer, the enzyme telomerase becomes activated and stabilizes telomeres, preserving damaged cells so they survive and reproduce.
In a strain of mice engineered to develop prostate cancer, all mice that went through this two-step process developed lethal cancer and 25% had the disease spread to the spine. Two groups of mice that avoided this cycle developed only precancerous lesions or localized prostate cancer.
A comparative analysis of genetic changes in the metastatic mouse tumors and those found in metastatic human prostate cancer identified that some genomic alterations, such as deletion of Smad4 gene, are drivers in the spread of cancer to the bones and associated with human prostate cancer prognosis.
“These in vivo mouse studies, together with human and mouse prostate cancer genomic data, provide evidence that telomere dysfunction plays a critical role in prostate cancer initiation and progression,” says co-senior author Lynda Chin, M.D., professor and chair of MD Anderson’s Department of Genomic Medicine and scientific director of the Institute for Applied Cancer Science.
“Our studies also show that telomerase activation after genomic instability caused by telomere dysfunction enables evolving cancers to progress and acquire new biological properties, including central features of advanced human prostate cancer,” Chin says.
Chin and MD Anderson President Ronald DePinho, M.D., and colleagues conducted this research while at Dana-Farber Cancer Institute in Boston.
Reported in the March 2, 2012, edition of Cell.
Telomeres — repetitive nucleotide sequences at the tips of chromosomes that prevent genomic damage during cell division. With each division the telomeres shorten, leading eventually to genomic instability and cell death, a period termed “telomere crisis.” Telomeres have been compared with the plastic tips on shoelaces. They prevent chromosome ends from fraying and sticking to each other, which would scramble an organism’s genetic information and cause diseases such as cancer.
Telomerase — an enzyme that adds DNA sequence repeats (“TTAGGG” in all vertebrates) to the ends of telomere regions to preserve their length across cell divisions. Telomerase activity is low or absent in normal cells, which have enough segments of repeat nucleotides (telomeres) at the ends of their chromosomes that protect DNA stability during cell division. In cancer, telomerase becomes active during telomere crisis and saves the genomically abnormal cells, allowing them to reproduce.
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