What is Telomerase?
Telomerase is an enzyme that adds repetitive nucleotide sequences to the ends of chromosomes, known as
telomeres. These telomeres protect the chromosome ends from deterioration and from fusion with neighboring chromosomes. Telomerase is composed of a protein component with reverse transcriptase activity (TERT) and an RNA component (TERC) that serves as a template for the addition of telomeric repeats.
How is Telomerase Activity Related to Cancer?
In most somatic cells, telomerase activity is low or absent, leading to gradual telomere shortening with each cell division, which eventually triggers cellular senescence or apoptosis. However, in over 85% of
cancer cells, telomerase activity is reactivated, allowing these cells to maintain telomere length and enabling them to divide indefinitely. This contributes to the
immortality of cancer cells, one of the hallmarks of cancer.
Genetic Mutations: Mutations in the promoter region of the TERT gene can increase its expression.
Epigenetic Changes: Alterations in DNA methylation and histone modification can lead to the upregulation of telomerase.
Regulatory Proteins: Overexpression or activation of certain
transcription factors can enhance TERT gene expression.
Why is Telomerase Activation a Target for Cancer Therapy?
Because telomerase activity is relatively low in normal somatic cells but high in cancer cells, it represents a potential target for cancer therapy. Inhibiting telomerase could limit the replicative potential of cancer cells, leading to their eventual senescence or death. Various strategies are being explored, including small molecule inhibitors, antisense oligonucleotides, and immunotherapeutic approaches targeting telomerase components.
Specificity: Ensuring that telomerase inhibitors specifically target cancer cells without affecting normal stem cells and germ cells, which also exhibit high telomerase activity, is crucial.
Resistance: Cancer cells may develop resistance to telomerase inhibitors, necessitating combination therapies.
Side Effects: Prolonged inhibition of telomerase could potentially lead to adverse effects on normal tissues that require telomerase for regeneration.
GRN163L (Imetelstat): A lipid-conjugated oligonucleotide that directly inhibits telomerase activity by binding to the RNA template component, TERC.
hTERT Vaccines: Vaccines that elicit an immune response against cells expressing the TERT protein.
Gene Editing: Techniques like CRISPR/Cas9 are being explored to disrupt the TERT gene specifically in cancer cells.
Conclusion
Telomerase activation plays a crucial role in the immortalization and proliferation of cancer cells, making it a promising target for therapeutic intervention. However, the complexity of telomerase regulation and the potential for adverse effects pose significant challenges. Continued research and clinical trials are essential to develop safe and effective telomerase-based therapies for cancer treatment.
