Nucleolar Stress Response via Ribosomal Protein L11 Regulates Topoisomerase Inhibitor Sensitivity of P53-Intact Cancers

• Published in: International journal of molecular sciences Vol. 23; no. 24; p. 15986
• Main Authors: Ishihara, Yuka, Nakamura, Kiyoshiro, Nakagawa, Shunsuke, Okamoto, Yasuhiro, Yamamoto, Masatatsu, Furukawa, Tatsuhiko, Kawahara, Kohichi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.12.2022; MDPI
• Subjects: Anthracycline; Anthracyclines - pharmacology; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Brain cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Nucleolus - metabolism; Cell proliferation; Cellular stress response; Chemical compounds; Depletion; Doxorubicin; drug sensitivity; Etoposide; Inhibitors; Leukemia; Lung cancer; Neoplasms - metabolism; nucleolar stress response; Nucleoli; Ovarian cancer; p53; p53 Protein; Pediatrics; Pharmacology; Protein L11; Proteins; Proto-Oncogene Proteins c-mdm2 - metabolism; Rhabdomyosarcoma; Ribosomal protein L11; Ribosomal Proteins - metabolism; RNA polymerase; RNA processing; RNA, Ribosomal - genetics; RPL11; rRNA; siRNA; Topoisomerase II Inhibitors - metabolism; Topoisomerase II Inhibitors - pharmacology; topoisomerase inhibitors; Topotecan; Transcription; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Western blotting; drug sensitivity; topoisomerase inhibitors; nucleolar stress response; RPL11; p53
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232415986

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.