Abstract
Nucleolar stress response is caused by perturbations in ribosome biogenesis, induced by the inhibition of ribosomal RNA processing and synthesis, as well as ribosome assembly. This response induces p53 stabilization and activation via ribosomal protein L11 (RPL11), suppressing tumor progression. However, anticancer agents that kill cells via this mechanism, and their relationship with the therapeutic efficiency of these agents, remain largely unknown. Here, we sought to investigate whether topoisomerase inhibitors can induce nucleolar stress response as they reportedly block ribosomal RNA transcription. Using rhabdomyosarcoma and rhabdoid tumor cell lines that are sensitive to the nucleolar stress response, we evaluated whether nucleolar stress response is associated with sensitivity to topoisomerase inhibitors ellipticine, doxorubicin, etoposide, topotecan, and anthracyclines. Cell proliferation assay indicated that small interfering RNA-mediated RPL11 depletion resulted in decreased sensitivity to topoisomerase inhibitors. Furthermore, the expression of p53 and its downstream target proteins via western blotting showed the suppression of p53 pathway activation upon RPL11 knockdown. These results suggest that the sensitivity of cancer cells to topoisomerase inhibitors is regulated by RPL11-mediated nucleolar stress responses. Thus, RPL11 expression may contribute to the prediction of the therapeutic efficacy of topoisomerase inhibitors and increase their therapeutic effect of topoisomerase inhibitors.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference41 articles.
1. DNA topoisomerase I and DNA gyrase as targets for TB therapy;Nagaraja;Drug Discov. Today,2017
2. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs;Pommier;Chem. Biol.,2010
3. Soren, B.C., Babu Dasari, J., Ottaviani, A., Messina, B., Andreotti, G., Romeo, A., Iacovelli, F., Falconi, M., Desideri, A., and Fiorani, P. (2021). In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB. Int. J. Mol. Sci., 22.
4. Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases;Corbett;Annu. Rev. Biophys. Biomol. Struct.,2004
5. Topoisomerases as anticancer targets;Delgado;Biochem. J.,2018
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