Abstract
The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers.
Highlights
Aptamers are relatively short DNA and RNA oligonucleotides endowed with high affinity and specificity toward a given target molecule [1]
In 2017, we described the antiproliferative activity of several thrombin binding aptamer (TBA) derivatives against two different cancer cell lines, namely Calu-6 and HCT 116p53−/− [11]
In p53-deleted colon cancer cells, the cytotoxic activity of LQ1 is mediated by the ribosomal protein uL3 and is associated to the activation of a p53-independent nucleolar stress pathway
Summary
Aptamers are relatively short DNA and RNA oligonucleotides endowed with high affinity and specificity toward a given target molecule [1]. By starting from random oligonucleotide sequences and through selection and amplification steps, this method allows the identification of ligands able to adopt peculiar tridimensional structures. Thanks to their outstanding properties, aptamers can be regarded as promising therapeutic and/or diagnostic tools, which are often considered a valid alternative to antibodies in several applications. One of the crucial features of aptamers during the SELEX process is their ability to fold in properly stable nucleic acid secondary structures. Not surprisingly, a considerable number of aptamers with significant biological activities are characterized by G-rich sequences, adopting G-quadruplex structures such as scaffolds (G4-aptamers), which are among the most stable nucleic acid coBinomfoolrecmuleast2i0o1n9,s9,[x3F]O.
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