Oncology reports, 2020-06, Vol.43 (6), p.1863-1874
2020
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- Autor(en) / Beteiligte
- Titel
- Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells
- Ist Teil von
- Oncology reports, 2020-06, Vol.43 (6), p.1863-1874
- Ort / Verlag
- Greece: Spandidos Publications
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Lung cancer has one of the highest mortalities of any cancer worldwide. Triptolide (TP) is a promising tumor suppressor extracted from the Chinese herb Tripterygium wilfordii. Our previous proteomics analysis revealed that TP significantly interfered with the ribosome biogenesis pathway; however, the underlying molecular mechanism remains poorly understood. The aim of the present study was to determine the molecular mechanism of TP's anticancer effect by investigating the association between ribosomal stress and p53 activation. It was found that TP induces nucleolar disintegration together with RNA polymerase I (Pol I) and upstream binding factor (UBF) translocation. TP interrupted ribosomal (r)RNA synthesis through inhibition of RNA Pol I and UBF transcriptional activation. TP treatment increased the binding of ribosomal protein L23 (RPL23) to mouse double minute 2 protein (MDM2), resulting in p53 being released from MDM2 and stabilized. Activation of p53 induced apoptosis and cell cycle arrest by enhancing the activation of p53 upregulated modulator of apoptosis, caspase 9 and caspase 3, and suppressing BCL2. In vivo experiments showed that TP significantly reduced xenograft tumor size and increased mouse body weight. Immunohistochemical assays confirmed that TP significantly increased the p53 level and induced nucleolus disintegration, during which nucleolin distribution moved from the nucleolus to the nucleoplasm, and RPL23 clustered at the edge of the cell membrane. Therefore, it was proposed that TP induces ribosomal stress, which leads to nucleolus disintegration, and inhibition of rRNA transcription and synthesis, resulting in increased binding of RPL23 with MDM2. Consequently, p53 is activated, which induces apoptosis and cell cycle arrest.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1021-335XeISSN: 1791-2431DOI: 10.3892/or.2020.7569Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7160537
- Format
- –
- Schlagworte
- A549 Cells, Animals, Antineoplastic Agents, Alkylating - administration & dosage, Antineoplastic Agents, Alkylating - pharmacology, Apoptosis, Biosynthesis, Body weight, Cancer cells, Cancer therapies, Cancer treatment, Cell cycle, Cell Cycle Checkpoints - drug effects, Cell growth, Cell membranes, Cell Proliferation - drug effects, Cell Survival - drug effects, Cold, Diterpenes - administration & dosage, Diterpenes - pharmacology, EDTA, Epoxy Compounds - administration & dosage, Epoxy Compounds - pharmacology, Fluorides, Gene Expression Regulation, Neoplastic - drug effects, Health aspects, Humans, Immunoglobulins, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - metabolism, Male, Mice, Pharmaceutical industry, Phenanthrenes - administration & dosage, Phenanthrenes - pharmacology, Protein binding, Proteins, Proteomics, Proto-Oncogene Proteins c-mdm2 - metabolism, Ribosomal Proteins - metabolism, RNA, RNA polymerase, RNA synthesis, RNA, Ribosomal - metabolism, Scientific equipment industry, Signal Transduction - drug effects, Transcription (Genetics), Tumor proteins, Tumor Suppressor Protein p53 - metabolism, Tumors, Xenograft Model Antitumor Assays