A cell-based screening system for RNA polymerase I inhibitors

Area of Science:

• Molecular Biology
• Biochemistry
• Cancer Research

Background:

• RNA polymerase I (RNA Pol I) transcribes ribosomal RNA, essential for protein synthesis and cell growth.
• Deregulation of RNA Pol I is linked to uncontrolled cell proliferation and cancer.
• Targeting RNA Pol I offers a potential strategy for cancer therapy.

Purpose of the Study:

• To develop a cell-based screening strategy for identifying selective RNA Pol I inhibitors.
• To validate a novel yeast model system for RNA Pol I inhibitor screening.
• To identify and evaluate new candidate RNA Pol I inhibitors.

Main Methods:

• Established a stable yeast cell line with integrated human RNA Pol I promoter and ribosomal DNA.
• Validated the model using the known inhibitor CX-5461 and measuring transcribed human rRNA.
• Employed virtual screening and compound library screening to identify inhibitors.
• Conducted growth and transcription activity assays to evaluate candidate compounds.

Main Results:

• Successfully developed and validated a yeast-based screening system for RNA Pol I inhibitors.
• Identified cerivastatin sodium as a novel candidate inhibitor of RNA Pol I.
• Demonstrated preliminary antiproliferative effects of cerivastatin sodium against human cancer cell lines (A2780 and H460).

Conclusions:

• Cerivastatin sodium is a selective RNA Pol I inhibitor with potential as an anticancer therapeutic.
• The developed yeast model system is effective for discovering RNA Pol I inhibitors.
• Further development of cerivastatin sodium is warranted for targeted cancer therapy.