Abstract
BackgroundTelomere/telomerase system has been recently recognized as an attractive target for anticancer therapy. Telomerase inhibition results in tumor regression and increased sensitivity to various cytotoxic drugs. However, it has not been fully established yet whether the mediator of these effects is telomerase inhibition per se or telomere shortening resulting from inhibition of telomerase activity. In addition, the characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner.Methodology/Principal FindingsIn this study we characterized the relative importance of telomerase inhibition versus telomere shortening in cancer cells. Sensitization of cancer cells to cytotoxic drugs was achieved by telomere shortening in a length dependent manner and not by telomerase inhibition per se. In our system this sensitization was related to the mechanism of action of the cytotoxic drug. In addition, telomere shortening affected also other cancer cell functions such as migration. Telomere shortening induced DNA damage whose repair was impaired after administration of cisplatinum while doxorubicin or vincristine did not affect the DNA repair. These findings were verified also in in vivo mouse model. The putative explanation underlying the phenotype induced by telomere shortening may be related to changes in expression of various microRNAs triggered by telomere shortening.Conclusions/SignificanceTo our best knowledge this is the first study characterizing the relative impact of telomerase inhibition and telomere shortening on several aspects of cancer cell phenotype, especially related to sensitivity to cytotoxic drugs and its putative mechanisms. The microRNA changes in cancer cells upon telomere shortening are novel information. These findings may facilitate the development of telomere based approaches in treatment of cancer.
Highlights
Human telomeres are composed of single stranded TTAGGG repeats and corresponding duplexes of this hexanucleotide located at both ends of the linear chromosome
Telomeres incrementally erode in most somatic cells upon each round of DNA replication, until they reach critical short length which eventually initiates a cessation of cell growth termed cellular senescence [2]
We suggest that telomere shortening in cancer cells is associated with changes in miRNA expression and leads to impaired DNA repair after exposure to cisplatinum
Summary
Human telomeres are composed of single stranded TTAGGG repeats and corresponding duplexes of this hexanucleotide located at both ends of the linear chromosome. Telomerase is a unique reverse transcriptase ribonucleoprotein complex that maintains a steady state of telomere length by synthesizing TTAGGG repeats at the ends of chromosomes. It is highly active in more than 90% of all malignancies, and considered a hallmark of cancer [3]. Telomerase is not expressed in most normal somatic cells but retains moderate activity in proliferative stem cells and to a higher extent in male germ line cells Due to this specificity and essentiality to the limitless lifespan of cancer cells, telomerase is considered a valid and attractive anticancer target [4]. The characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner
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