Triptolide interrupts rRNA synthesis and induces the RPL23‑MDM2‑p53 pathway to repress lung cancer cells

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• Lung cancer exhibits high global mortality.
• Triptolide (TP), a tumor suppressor from Tripterygium wilfordii, shows potential but its mechanism is unclear.
• Previous studies indicated TP interferes with ribosome biogenesis.

Purpose of the Study:

• To elucidate the molecular mechanism of TP's anticancer effects.
• To investigate the link between ribosomal stress and p53 activation by TP.
• To understand TP's impact on rRNA synthesis and apoptosis pathways.

Main Methods:

• Investigated TP's effects on nucleolar structure and RNA polymerase I (Pol I) activity.
• Assessed the interaction between ribosomal protein L23 (RPL23) and MDM2.
• Analyzed p53 activation, downstream apoptosis markers (caspase 9, caspase 3, BCL2), and cell cycle arrest.
• Conducted in vivo xenograft tumor models and immunohistochemical analyses.

Main Results:

• TP induced nucleolar disintegration and translocation of RNA Pol I and UBF.
• TP inhibited rRNA synthesis by suppressing RNA Pol I and UBF transcriptional activity.
• TP treatment increased RPL23 binding to MDM2, stabilizing and activating p53.
• Activated p53 enhanced apoptosis and cell cycle arrest.
• In vivo studies showed TP reduced tumor size and increased mouse weight.
• Immunohistochemistry confirmed increased p53 levels and nucleolar disintegration in tumors.

Conclusions:

• TP induces ribosomal stress, leading to nucleolar disintegration and inhibited rRNA synthesis.
• TP-induced ribosomal stress activates p53 through the RPL23-MDM2 interaction.
• Activated p53 triggers apoptosis and cell cycle arrest, demonstrating TP's anticancer efficacy.
• TP presents a promising therapeutic agent for lung cancer by targeting ribosome biogenesis and p53 activation.