Abstract
Telomeres, the specialized dynamic structures at chromosome ends, regularly shrink with every replication. Thus, they function as an internal molecular clock counting down the number of cell divisions. However, most cancer cells escape this limitation by activating telomerase, which can maintain telomere length. Previous studies showed that the benzylisoquinoline alkaloid chelidonine stimulates multiple modes of cell death and strongly down-regulates telomerase. It is still unknown if down-regulation of telomerase by chelidonine boosts substantial telomere shortening. The breast cancer cell line MCF7 was sequentially treated with very low concentrations of chelidonine over several cell passages. Telomere length and telomerase activity were measured by a monochrome multiplex quantitative PCR and a q-TRAP assay, respectively. Changes in population size and doubling time correlated well with telomerase inhibition and telomere shortening. MCF7 cell growth was arrested completely after three sequential treatments with 0.1 μM chelidonine, each ending after 48 h, while telomere length was reduced to almost 10% of the untreated control. However, treatment with 0.01 μM chelidonine did not have any apparent consequence. In addition to dose and time dependent telomerase inhibition, chelidonine changed the splicing pattern of hTERT towards non-enzyme coding isoforms of the transcript. In conclusion, telomere length and telomere stability are strongly affected by chelidonine in addition to microtubule formation.
Highlights
Telomeres are specialized nucleoprotein structures at the ends of linear eukaryotic chromosomes which were first observed in 1938 by Muller [1,2]
Telomere shortening by low doses of chelidonine the so-called shelterin complex [5,6,7,8]
Exponentially growing cells were seeded in 96 well plates, 10000 cells per well, and after 24 h incubated in medium containing various concentrations of chelidonine freshly prepared by dilutions (100, 50, 25, 12.5, 6.25, 3.12, 1.56, 0.78, 0.39, 0.2 and 0.02 μM) from a stock solution (50 mM in absolute ethanol), while the final concentration of ethanol was Telomere shortening by low doses of chelidonine always less than 0.01%
Summary
Telomeres are specialized nucleoprotein structures at the ends of linear eukaryotic chromosomes which were first observed in 1938 by Muller [1,2]. Their function is essential for the stability and protection of chromosomes from degradation by DNases [2,3], preventing endjoining [3] and aberrant recombination of chromosomes [2,4]. In cycling cells, telomere shortening because of the end-replication problem leads to reduction of telomere length by 50–100 base pairs after every cell division [1,2,9,10,11]. Short telomeres activate intracellular signalling pathways which can induce cell cycle arrest and programmed cell death [14,15]
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