Telomerase inhibition – a cancer therapy that is not always what it seems (05/2004)
Telomerase is a protein involved in cancer where it is present in 85 to 90% of all cases. Taking advantage of this fact, over the last years multiple new approaches have appeared that aim to inhibit telomerase activity as a new treatment strategy in human cancer.
However, in the latest issue of the journal Oncogene 1 (20th May) scientists reveal that in some types of cancers anti-telomerase therapy, instead of kill cancerous cells puts them into senescence, a physiological state where cells although unable to divide and consequently grow, are nevertheless metabolically active. This would imply the need for expensive long-term treatment and, because cancerous cells are alive, the possibility that resistant clones and subsequent tumour re-growth might occur. These results call for further investigations into the effect of anti-telomerase therapy in different cancers before the treatment becomes widely used.
Telomerase is a unique enzyme that acts on specialised structures called telomeres. Telomeres are repetitive pieces of DNA at the end of chromosomes that do not correspond to any gene but, instead, act as protective caps. Without telomeres, chromosomes ends would be perceived as broken DNA and unnecessary repair would lead to DNA damage and cell death.
Additionally, telomeres also serve as the cells’ “life clock" by limiting the number of divisions that a normal cell can undergo. During cell division, chromosomes are duplicated so copies of the parent genetic information go into each of the daughter cells. But, like a tape recorder that is unable to play the last part of the tape, it is also not possible to copy the last end of the chromosome. This means that with each cell division, chromosomes, or more exactly telomeres, get shorter and shorter. When they reach such a critical length that can compromise chromosome stability, the cell stops dividing and become senescent – non-dividing but still metabolically active. A key molecule involved in this process is p53. Whenever there is chromosome damage (like when telomeres become too short), p53 is activated stopping cell division (cells enter senescence) until the damage is repaired or, if this is not possible, the cell is induced to die. If p53 itself does not function correctly, cells will continue to grow with damaged DNA until their telomeres are so short that chromosome instability leads invariably to cell death.
But some cells never go into senescence or death even after multiple divisions. They escape through the activation of telomerase, an enzyme capable of adding new DNA repeats to telomeres thus maintaining their length. In this way p53 and/or other similar control mechanism are eluded and the cell can go on multiplying forever. Telomerase is especially important in foetal tissues, reproductive cells and other tissues where extensive cell proliferation is necessary.
Unfortunately, telomerase is also present in 85 to 90% of all cancers where it gives cancerous cells that elusive and so special quality: “immortality”. Examples include ovarian and liver carcinoma, leukaemia and cancers of the breast, prostate, thyroid, lung, kidneys and bladder. Malignancy is normally the final result of an accumulation of multiple mutations and telomerase gives cancerous cells that elusive and so special quality: “immortality”.
At the same time, because telomerase is the most widely expressed tumour marker known, present at only low or undetectable levels in normal cells multiple possibilities for the development of new anti-cancer drugs based on its inhibition were raised with the discovery of this enzime. Anti-telomerase therapies also seem to have much fewer adverse side effects than more traditional treatments such as chemo- or radio-therapy. This has made anti-cancer therapies based on telomerase inhibition an area of great promise in medicine.
But Ana Preto at the Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal, Christopher J Jones at the University of Wales College of Medicine, Cardiff UK and colleagues noticed that anti-telomerase research has been limited to tumours with a mutated/non-functional p53. This was probably due not only to the fact that this group made the majority of the cancers but also that to scientists investigating the effect of anti-telomerase therapies, a non-functional p53 has the advantage of avoiding DNA-repair mechanisms and causes cancerous cells, after telomerase inhibition, to go directly into the death process.
However, an important minority of tumours, like some breast, thyroid and melanoma, conserve an intact p53 molecule and this led Preto, Jones and colleagues to ask what would be the effect of anti-telomerase therapy on these tumours. This is an important question as some of the cancers with a non-mutated p53 do not respond well to conventional treatments and anti-telomerase therapy has been seen as a promising complementary alternative.
To answer it the team of scientists investigated cultures of telomerase-positive cells from several thyroid cancers with an intact/non-mutated p53. By inhibiting telomerase activity in these cancerous cells the team of scientists observed, as expected, telomere erosion/shortening following cell division. But to their surprise anti-telomerase therapy did not result in cell death, in contrast to what is observed in tumours with mutated p53, but instead the outcome was senescence. Blocking p53 in these cells resulted in cell death rather than senescence, which proved the role of this molecule in the process.
An outcome of senescence following cancer therapy has many potential problems. Although it represents an arrest of tumour’s growth, cells are, nevertheless, very much alive and metabolically active and can stay like that for very long periods of time, even years. This implies expensive long-term treatments to assure that this non-dividing cellular state is maintained, during which emergence of cells resistant to the treatment and subsequent tumour re-growth can occur. While cell death is a definitive process of getting rid of cancerous cells, senescence, on the other hand, can be a “well” of unpredictability.
Many of the cancers that conserve an intact p53, for example the extremely aggressive melanoma and some solid tumours types, do not respond well to traditional therapies. In these cases, anti-telomerase was seen as an important complementary treatment to try and increase the rate of therapeutic success. Preto, Jones and colleagues’ results highlighting the possible drawbacks of anti-telomerase therapy are very important and need to be taken into account in the design of future therapies.
1 Oncogene23, 4136 - 4145 (20 May 2004)
“Telomere erosion triggers growth arrest but not cell death in human cancer cells retaining wild-type p53: implications for antitelomerase therapy”
Original paper’s authors
In collaboration with the Observatório da Ciência e do Ensino Superior (OCES)
Financed by the Fundação para a Ciência e Tecnologia (FCT)