uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells
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,...
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| Format: | Article |
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MDPI AG
2020-04-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/4/583 |
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| author | Annalisa Pecoraro Antonella Virgilio Veronica Esposito Aldo Galeone Giulia Russo Annapina Russo |
| author_facet | Annalisa Pecoraro Antonella Virgilio Veronica Esposito Aldo Galeone Giulia Russo Annapina Russo |
| author_sort | Annalisa Pecoraro |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T20:34:10Z |
| format | Article |
| id | doaj.art-ad7005daf14b4fa590cb1bb90c6f1559 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T20:34:10Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-ad7005daf14b4fa590cb1bb90c6f15592023-11-19T21:12:36ZengMDPI AGBiomolecules2218-273X2020-04-0110458310.3390/biom10040583uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer CellsAnnalisa Pecoraro0Antonella Virgilio1Veronica Esposito2Aldo Galeone3Giulia Russo4Annapina Russo5Department of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano 49, 80131 Naples, ItalyThe 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.https://www.mdpi.com/2218-273X/10/4/583G-quadruplex aptamersTBA derivativesnucleolar stressribosomal protein uL3cancer therapy |
| spellingShingle | Annalisa Pecoraro Antonella Virgilio Veronica Esposito Aldo Galeone Giulia Russo Annapina Russo uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells Biomolecules G-quadruplex aptamers TBA derivatives nucleolar stress ribosomal protein uL3 cancer therapy |
| title | uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells |
| title_full | uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells |
| title_fullStr | uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells |
| title_full_unstemmed | uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells |
| title_short | uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells |
| title_sort | ul3 mediated nucleolar stress pathway as a new mechanism of action of antiproliferative g quadruplex tba derivatives in colon cancer cells |
| topic | G-quadruplex aptamers TBA derivatives nucleolar stress ribosomal protein uL3 cancer therapy |
| url | https://www.mdpi.com/2218-273X/10/4/583 |
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